Aromatic 5-membered heterocyclic derivative having trpv4-inhibiting activity

ABSTRACT

The present invention is related to a compound represented by formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1  is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclyl, or the like; X is —N(R 3 )—, —O—, or —S—; Y is ═C(R 4 )—, or ═N—; Z is —N(R 7 )—, —O—, or —S—;
     R 2  is substituted or unsubstituted alkyloxy, or the like, or a group represented by the following formula: —(CR 2a R 2b ) n —R 2c , wherein R 2a  is each independently a hydrogen atom, halogen, or the like; R 2b  is each independently a hydrogen atom, halogen, or the like; R 2a  and R 2b  which are attached to the same carbon atom may be taken together to form oxo, a substituted or unsubstituted non-aromatic carbocycle, or the like; two of R 2a  which are attached to the adjacent carbon atoms and/or two of R 2b  which are attached to the adjacent carbon atoms may be taken together to form a bond; R 2c  is substituted or unsubstituted aromatic carbocyclyl, or the like; n is an integer from 1 to 3;   R 3  and R 7  are each independently a hydrogen atom, substituted or unsubstituted alkyl, or the like;   R 4  and R 5  are each independently a hydrogen atom, halogen, substituted or unsubstituted alkyl, or the like;   R 6  is a hydrogen atom, halogen, substituted or unsubstituted alkyl, or the like,
 
or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

TECHNICAL FIELD

The present invention relates to a compound that has a TRPV4 inhibitoryactivity and is useful in the treatment and/or prevention of a TRPV4receptor-mediated disorder, or a pharmaceutically acceptable saltthereof, and a pharmaceutical composition containing thereof.

BACKGROUND ART

TRPV4 is one of a cation channel of the TRP (Transient ReceptorPotential) superfamily. It was discovered as an osmotic-sensitivityreceptor activated by hypotonic stimulus. Then, it was shown that TRPV4had a temperature-sensitive property, that is, TRPV4 was activated atthe body temperature rage, and TRPV4 is activated by heat and low pH. Itis reported that the gene and protein of TRPV4 is expressed in brain,spinal code, peripheral nerve fiber, skin, kidney, trachea, cochlea andbone, etc. Moreover, it is also reported that TRPV4 is activated by thecompounds, such as arachidonic acid, arachidonate metabolite,endocannabinoids, and phorbol ester. The increase of activation of theC-fiber by hypotonic stimulation under the inflammatory environmentinduced by inflammatory mediators, is known, and it is also reportedthat TRPV4 relates to this activation. Furthermore, it is also reportedthat TRPV4 is activated by fluid pressure and mechanical stimuli, andTRPV4 relates to hyperalgesia caused by mechanical stimuli. In addition,it is also reported that TRPV4 relates to paclitaxel-induced pain(Non-patent documents 1 to 5). Therefore, it is expected that TRPV4participates in many physiological roles. The compound which exhibitshigh affinity to TRPV4 has a high potential as useful medicine in thetherapy and/or prevention of TRPV4 receptor-mediated disorder.

The compounds having TRPV4 inhibitory activity are disclosed inpatent-documents 1 to 11, 20, 22 to 25 and non-patent documents 6 to 9.The compounds suggested to be related with TRPV4 are disclosed inpatent-documents 12 to 19. However, the compounds of this presentinvention are not disclosed in any documents.

The derivatives wherein two thiazole rings are directly attached aredisclosed in patent-document 21. However, there is neither disclosurenor suggestion about a TRPV4 inhibitory activity.

PRIOR ART REFERENCES Patent Document

-   [Patent Document 1] International Publication No. 2009/111680    pamphlet-   [Patent Document 2] International Publication No. 2009/146177    pamphlet-   [Patent Document 3] International Publication No. 2009/146182    pamphlet-   [Patent Document 4] International Publication No. 2010/011912    pamphlet-   [Patent Document 5] International Publication No. 2010/011914    pamphlet-   [Patent Document 6] International Publication No. 2011/091407    pamphlet-   [Patent Document 7] International Publication No. 2011/091410    pamphlet-   [Patent Document 8] International Publication No. 2011/119693    pamphlet-   [Patent Document 9] International Publication No. 2011/119694    pamphlet-   [Patent Document 10] International Publication No. 2011/119701    pamphlet-   [Patent Document 11] International Publication No. 2011/119704    pamphlet-   [Patent Document 12] International Publication No. 2006/038070    pamphlet-   [Patent Document 13] International Publication No. 2007/059608    pamphlet-   [Patent Document 14] International Publication No. 2007/071055    pamphlet-   [Patent Document 15] International Publication No. 2007/115403    pamphlet-   [Patent Document 16] International Publication No. 2007/115408    pamphlet-   [Patent Document 17] International Publication No. 2007/115409    pamphlet-   [Patent Document 18] International Publication No. 2007/115410    pamphlet-   [Patent Document 19] International Publication No. 2008/144931    pamphlet-   [Patent Document 20] JP-A No. 2009-084209-   [Patent Document 21] JP-A No. 2002-053566-   [Patent Document 22] International Publication No. 2012/144661    pamphlet-   [Patent Document 23] International Publication No. 2012/174340    pamphlet-   [Patent Document 24] International Publication No. 2012/174342    pamphlet-   [Patent Document 25] International Publication No. 2013/012500    pamphlet

Non-Patent Document

-   [Non-patent Document 1] Progress in Biophysics and Molecular    Biology, 2010, 103, pp. 2-17-   [Non-patent Document 2] Cell Calcium, 2003, 33, pp. 79-487-   [Non-patent Document 3] Seikagaku, 2009, 81(11), pp. 962-98,-   [Non-patent Document 4] Folia Pharmacologica Japonica, 2006, 127,    pp. 128-132-   [Non-patent Document 5] Seibutsu Butsuri, 2005, 45(5), pp. 268-271-   [Non-patent Document 6] ARTHRITIS & RHEUMATISM, 2009, 60, pp.    3028-3037-   [Non-patent Document 7] Biochemical and Biophysical Research    Communications, 2009, 389, pp. 490-494-   [Non-patent Document 8] Proceedings of the National Academy of    Sciences, 2010, 107, pp. 19084-19089-   [Non-patent Document 9] MedChemComm, 2013, 4, pp, 244-251

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The purpose of the present invention is to provide a compound that has aTRPV4 inhibitory activity or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition containing thereof that has a TRPV4inhibitory activity.

Means for Solving the Problem

The present inventors have eagerly made progress in their studies,resulting in finding that a compound that has a TRPV4 inhibitoryactivity and is useful in the treatment and/or prevention of a TRPV4receptor-mediated disorder, or a pharmaceutically acceptable saltthereof, and have accomplished the following invention.

The present invention relates to the following 1) to 30).

1) A compound represented by formula (I):

wherein R¹ is a hydrogen atom, substituted or unsubstituted alkyl,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, or substituted or unsubstituted non-aromaticheterocyclyl;

—X— is —N(R³)—, —O—, or —S—;

═Y— is ═C(R⁴)—, or ═N—;

—Z— is —N(R⁷)—, —O—, or —S—;

R² is substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted amino, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, substituted orunsubstituted non-aromatic heterocyclyl, substituted or unsubstitutedaromatic carbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylsulfanyl, substituted orunsubstituted non-aromatic carbocyclylsulfanyl, substituted orunsubstituted aromatic heterocyclylsulfanyl, or substituted orunsubstituted non-aromatic heterocyclylsulfanyl, or

a group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein R^(2a) is each independently a hydrogen atom, halogen, hydroxy,carboxy, sulfanyl, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, substituted or unsubstitutedalkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy,substituted or unsubstituted alkynylcarbonyloxy, substituted orunsubstituted alkyloxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl,substituted or unsubstituted carbamoyl, substituted or unsubstitutedsulfamoyl, substituted or unsubstituted aromatic carbocyclyl,substituted or unsubstituted non-aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic heterocyclyl, substituted or unsubstituted aromaticcarbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylcarbonyl, substituted orunsubstituted non-aromatic carbocyclylcarbonyl, substituted orunsubstituted aromatic heterocyclylcarbonyl, substituted orunsubstituted non-aromatic heterocyclylcarbonyl, substituted orunsubstituted aromatic carbocyclyloxycarbonyl, substituted orunsubstituted non-aromatic carbocyclyloxycarbonyl, substituted orunsubstituted aromatic heterocyclyloxycarbonyl, substituted orunsubstituted non-aromatic heterocyclyloxycarbonyl, substituted orunsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstitutednon-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;

R^(2b) is each independently a hydrogen atom, halogen, hydroxy, carboxy,sulfanyl, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substitutedor unsubstituted alkynylcarbonyl, substituted or unsubstituted amino,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;

R^(2a) and R^(2b) which are attached to the same carbon atom may betaken together to form oxo, substituted or unsubstituted imino, asubstituted or unsubstituted non-aromatic carbocycle, or a substitutedor unsubstituted non-aromatic heterocycle,

two of R^(2a) which are attached to the adjacent carbon atoms and/or twoof R^(2b) which are attached to the adjacent carbon atoms may be takentogether to form a bond;

R^(2c) is a hydrogen atom, halogen, hydroxy, carboxy, sulfanyl, sulfino,sulfo, cyano, hydrazino, ureido, amidino, guanidino, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkyloxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted orunsubstituted alkenylcarbonyl, substituted or unsubstitutedalkynylcarbonyl, substituted or unsubstituted amino, substituted orunsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted imino, substituted or unsubstitutedalkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy,substituted or unsubstituted alkynylcarbonyloxy, substituted orunsubstituted alkyloxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted carbamoyl, substituted or unsubstitutedsulfamoyl, substituted or unsubstituted aromatic carbocyclyl,substituted or unsubstituted non-aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic heterocyclyl, substituted or unsubstituted aromaticcarbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylcarbonyl, substituted orunsubstituted non-aromatic carbocyclylcarbonyl, substituted orunsubstituted aromatic heterocyclylcarbonyl, substituted orunsubstituted non-aromatic heterocyclylcarbonyl, substituted orunsubstituted aromatic carbocyclyloxycarbonyl, substituted orunsubstituted non-aromatic carbocyclyloxycarbonyl, substituted orunsubstituted aromatic heterocyclyloxycarbonyl, substituted orunsubstituted non-aromatic heterocyclyloxycarbonyl, substituted orunsubstituted aromatic carbocyclylcarbonyloxy, substituted orunsubstituted non-aromatic carbocyclylcarbonyloxy, substituted orunsubstituted aromatic heterocyclylcarbonyloxy, substituted orunsubstituted non-aromatic heterocyclylcarbonyloxy, substituted orunsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstitutednon-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;

n is an integer from 1 to 3;

R³ and R⁷ are each independently a hydrogen atom, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkylsulfonyl,substituted or unsubstituted alkenylsulfonyl, substituted orunsubstituted alkynylsulfonyl, substituted or unsubstituted carbamoyl,substituted or unsubstituted sulfamoyl, substituted or unsubstitutedaromatic carbocyclyl, substituted or unsubstituted non-aromaticcarbocyclyl, substituted or unsubstituted aromatic heterocyclyl, orsubstituted or unsubstituted non-aromatic heterocyclyl;

R⁴ and R⁵ are each independently a hydrogen atom, halogen, hydroxy,carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, cyano, nitro,azido, amidino, guanidino, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, substituted or unsubstituted imino,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;

R⁶ is a hydrogen atom, halogen, hydroxy, formyl, formyloxy, sulfanyl,thioformyl, cyano, substituted or unsubstituted amidino, substituted orunsubstituted guanidino, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkyloxy, substituted or unsubstitutedalkenyloxy, substituted or unsubstituted alkynyloxy, substituted orunsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;

provided that the following compounds are excluded:

or a pharmaceutically acceptable salt thereof.Herein, in the case that “two of R^(2a) which are attached to theadjacent carbon atoms and/or two of R^(2b) which are attached to theadjacent carbon atoms may be taken together to form a bond”,“—(CR^(2a)R^(2b))_(n)—” does not form consecutive double bonds.2) The compound according to 1),wherein R¹ is a hydrogen atom,or a pharmaceutically acceptable salt thereof.3) The compound according to 1) or 2),wherein —Z— is —O— or —S—,or a pharmaceutically acceptable salt thereof.4) The compound according to any one of 1) to 3),wherein R² is substituted or unsubstituted amino, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl,ora group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein R^(2a) is each independently a hydrogen atom, halogen, hydroxy,carboxy, sulfanyl, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted amino, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted non-aromatic carbocyclyl, or substituted or unsubstitutednon-aromatic heterocyclyl;

R^(2b) is each independently a hydrogen atom, halogen, hydroxy, carboxy,sulfanyl, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedamino, substituted or unsubstituted alkylsulfanyl, substituted orunsubstituted alkenylsulfanyl, substituted or unsubstitutedalkynylsulfanyl, substituted or unsubstituted carbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted non-aromaticcarbocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl;

R^(2a) and R^(2b) which are attached to the same carbon atom at any oneposition may be taken together to form oxo, substituted or unsubstitutedimino, a substituted or unsubstituted non-aromatic carbocycle, or asubstituted or unsubstituted non-aromatic heterocycle;

R^(2c) is a hydrogen atom, halogen, hydroxy, carboxy, cyano, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedamino, substituted or unsubstituted alkylsulfonyl, substituted orunsubstituted alkenylsulfonyl, substituted or unsubstitutedalkynylsulfonyl, substituted or unsubstituted carbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, substituted orunsubstituted non-aromatic heterocyclyl, substituted or unsubstitutedaromatic carbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylsulfanyl, substituted orunsubstituted non-aromatic carbocyclylsulfanyl, substituted orunsubstituted aromatic heterocyclylsulfanyl, substituted orunsubstituted non-aromatic heterocyclylsulfanyl, substituted orunsubstituted non-aromatic carbocyclylsulfonyl, substituted orunsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstitutedaromatic heterocyclylsulfonyl, or substituted or unsubstitutednon-aromatic heterocyclylsulfonyl;

n is an integer from 1 to 3;

or a pharmaceutically acceptable salt thereof.5) The compound according to any one of 1) to 4),wherein R⁴ and R⁵ are each independently a hydrogen atom, halogen,cyano, substituted or unsubstituted alkyl, substituted or unsubstitutedamino, substituted or unsubstituted carbamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclylcarbonyl, substitutedor unsubstituted non-aromatic carbocyclylcarbonyl, substituted orunsubstituted aromatic heterocyclylcarbonyl, substituted orunsubstituted non-aromatic heterocyclylcarbonyl, substituted orunsubstituted aromatic carbocyclyloxycarbonyl, substituted orunsubstituted non-aromatic carbocyclyloxycarbonyl, substituted orunsubstituted aromatic heterocyclyloxycarbonyl, or substituted orunsubstituted non-aromatic heterocyclyloxycarbonyl,or a pharmaceutically acceptable salt thereof.6) The compound according to any one of 1) to 5),wherein R⁶ is a hydrogen atom, halogen, hydroxy, carboxy, sulfanyl,sulfino, sulfo, cyano, substituted or unsubstituted amidino, substitutedor unsubstituted guanidino, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkyloxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl,substituted or unsubstituted alkenylsulfanyl, substituted orunsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, or substituted or unsubstituted sulfamoyl,or a pharmaceutically acceptable salt thereof.7) A compound represented by formula (III):

wherein a and b are each independently 0, 1, 2 or 3;

—X— is —N(R³)— or —S—;

R³ is a hydrogen atom, alkyl, or

a group represented by the following formula:—(C(R^(3a))(R^(3b)))_(r)—OR^(3c), —(C(R^(3a))(R^(3b)))_(r)—CN, or—(C(R^(3a))(R^(3b)))_(r)-E-(R^(3c))_(d)wherein R^(3a) is each independently a hydrogen atom, halogen, alkyl orhaloalkyl,

R^(3b) is each independently a hydrogen atom, halogen, alkyl orhaloalkyl, or two of R^(3a) which are attached to the adjacent carbonatoms and/or two of R^(3b) which are attached to the adjacent carbonatoms may be taken together to form a bond;

R^(3c) is each independently a hydrogen atom, alkyl or haloalkyl;

E is an aromatic carbocycle, a non-aromatic carbocycle, an aromaticheterocycle or a non-aromatic heterocycle;

d and r are each independently 0, 1, 2 or 3;

═Y— is ═CH— or ═N—;

—Z— is —O— or —S—;

ring A is an aromatic carbocycle, a non-aromatic carbocycle, an aromaticheterocycle, or a non-aromatic heterocycle;

R^(2d) is each independently a hydrogen atom, halogen, nitro, alkyl,haloalkyl, or a group represented by the following formula:—(C(R^(2e))(R^(2f)))_(c)—OR^(2g), —SR^(2g),—O—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d), —C(═O)—R^(2g),—C(═O)-E-(R^(2k))_(d), (C(R^(2e))(R^(2f)))_(c)—C(═O)—OR^(2g),—C(═O)—N(R^(2g))(R^(2h)),—C(═O)—N(R^(2g))—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d),—(C(R^(2e))(R^(2f)))_(c)—SO₂R^(2g), —SO₂-E-(R^(2k))_(d),—SO₂N(R^(2g))(R^(2h)),—SO₂N(R^(2g))—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d),—(C(R^(2e))(R^(2f)))_(c)—N(R^(2g))(R^(2h)),—N(R^(2g))—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d),—N(R^(2g))—C(═O)—R^(2h), —N(R^(2g))—C(═O)-E-(R^(2k))_(d),(C(R^(2e))(R^(2f)))_(c)—N(R^(2g))—C(═O)—OR^(2h), —N(R^(2g))—SO₂R^(2h),—N(R^(2g))—SO₂-E-(R^(2k))_(d), —(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d),—(C(R^(2e))(R^(2f)))_(c)—CN,—(C(R^(2e))(R^(2f)))_(c)—O—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d),—O—(C(R^(2e))(R^(2f)))—OR^(2g),—O—(C(R^(2e))(R^(2f)))_(c)—N(R^(2g))(R^(2h)), or—(C(R^(2e))(R^(2f)))_(c)—N(R^(2g))-E-(R^(2k))_(d), or

two of R^(2d) which are attached to the same carbon atom may be takentogether to form oxo;wherein c is 0, 1, 2 or 3, d is the same as the above-mentioned;

R^(2e) is each independently a hydrogen atom, halogen, alkyl orhaloalkyl,

R^(2f) is each independently a hydrogen atom, halogen, alkyl orhaloalkyl, or, two of R^(2e) which are attached to the adjacent carbonatoms and/or two of R^(2f) which are attached to the adjacent carbonatoms may be taken together to form a bond;

R^(2g) is a hydrogen atom, alkyl or haloalkyl;

R^(2h) is a hydrogen atom, alkyl or haloalkyl;

R^(2k) is each independently halogen, alkyl, haloalkyl, oxo, —CN, or

a group represented by the following formula: —OR^(2m), —C(═O)—OR^(2m),—SO₂R^(2m), -E-R^(2m), or —N(R^(2m))(R^(2n)), ortwo of R^(2k) which are attached to the same carbon atom may be takentogether to form oxo,wherein E is the same as the above-mentioned;

R^(2m) is a hydrogen atom, alkyl or haloalkyl;

R^(2n) is a hydrogen atom, alkyl or haloalkyl;

R⁵ is a hydrogen atom, halogen, alkyl, haloalkyl, or

a group represented by the following formula:—(C(R^(5e))(R^(5f)))_(e)—OR^(5g),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))(R^(5h)),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—R^(5h),—(C((R^(5e))(R^(5f)))_(e)—C(═O)—N(R^(5g))(R^(5h)),—(C(R^(5e))(R^(5f)))_(e)—O—C(═O)—N(R^(5g))(R^(5h)),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—N(R^(5h))(R^(5k)),—(C(R^(5e))(R^(5f)))_(e)—C(═O)—R^(5g),—(C(R^(5e))(R^(5f)))_(e)—C(═O)-G-(R^(5m))_(h),—(C(R^(5e))(R^(5f)))_(e)—CN, —(C(R^(5e))(R^(5f)))_(e)-G-(R^(5m))_(h),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—SO₂N(R^(5h))(R^(5k)),—(C(R^(5e))(R^(5f)))_(e)—SO₂R^(5g),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—OR^(5h),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)-G-(R^(5m))_(h),—(C(R^(5e))(R^(5f)))_(e)—C(═O)—OR^(5g),—(C(R^(5e))(R^(5f)))_(e)—C(═O)—N(R^(5g))—(CH₂)_(h)—O(R^(5h)),—(C(R^(5e))(R^(5f)))_(e)—C(═O)—N(R^(5g))—(CH₂)_(h)—N(R^(5h))(R^(5k)),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—(CH₂)—OR^(5h), or—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—(CH₂)—O—C(═O)—N(R^(5h))(R^(5k));wherein R^(5e) is each independently a hydrogen atom, halogen, alkyl orhaloalkyl,

R^(5f) is each independently a hydrogen atom, halogen, alkyl orhaloalkyl, or two of R^(5e) which are attached to the adjacent carbonatoms and/or two of R^(5f) which are attached to the adjacent carbonatoms may be taken together to form a bond;

R^(5g) is a hydrogen atom, alkyl or haloalkyl;

R^(5h) is a hydrogen atom, alkyl or haloalkyl;

R^(5k) is a hydrogen atom, alkyl or haloalkyl;

R^(5m) is halogen, alkyl, haloalkyl, or

a group represented by the following formula: —OR^(5n), —C(═O)—OR^(5n),—SO₂R^(5n), or —N(R^(5n))(R^(5p)), ortwo of R^(5m) which are attached to the same carbon atom may be takentogether to form oxo,wherein R^(5n) is a hydrogen atom, alkyl or haloalkyl;

R^(5p) is a hydrogen atom, alkyl or haloalkyl);

G is an aromatic carbocycle, a non-aromatic carbocycle, an aromaticheterocycle or a non-aromatic heterocycle;

e and h are each independently 0, 1, 2 or 3;

R⁶ is a hydrogen atom, halogen, alkyl, haloalkyl, alkenyl, amidino,guanidino, or

a group represented by the following formula:—(C(R^(6e))(R^(6f)))_(f)—OR^(6g),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))(R^(6h)),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—C(═O)—R^(6h),—(C(R^(6e))(R^(6f)))_(f)—C(═O)—N(R^(6g))(R^(6h)),—(C(R^(6e))(R^(6f)))_(f)—O—C(═O)—N(R^(6g))(R^(6h)),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—C(═O)—N(R^(6h))(R^(6k)),—(C(R^(6e))(R^(6f)))_(f)—C(═O)—R^(6g),—(C(R^(6e))(R^(6f)))_(f)—C(═O)-G-(R^(6m))_(k),—(C(R^(6e))(R^(6f)))_(f)—CN, —(C(R^(6e))(R^(6f)))_(f)-G-(R^(6m))_(k),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—SO₂N(R^(6h))(R^(6k)),—(C(R^(6e))(R^(6f)))_(f)—SO₂R^(6g),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—SO₂R^(6h),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—C(═O)—OR^(6h),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—C(═O)-G-(R^(6m))_(k),—(C(R^(6e))(R^(6f)))_(f)—C(═O)—OR^(6g),—(C(R^(6e))(R^(6f)))_(f)—C(═O)—N(R^(6g))—(CH₂)_(f)—OR^(6h),—(C(R^(6e))(R^(6f)))_(f)—C(═O)—N(R^(6g))—(CH₂)_(f)—N(R^(6h))(R^(6k)),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—C(═O)—(CH₂)—OR^(6h),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—C(═O)—(CH₂)—O—C(═O)—N((R^(6h))(R^(6k)),or —(C(R^(6e))(R^(6f)))_(f)—O—(CH₂)₂—OR^(6g)wherein R^(6e) is each independently a hydrogen atom, halogen, alkyl orhaloalkyl,

R^(6f) is each independently a hydrogen atom, halogen, alkyl orhaloalkyl, or two of R^(6e) which are attached to the adjacent carbonatoms and/or two of R^(6f) which are attached to the adjacent carbonsatom may be taken together to form a bond;

R^(6g) is a hydrogen atom, alkyl or haloalkyl;

R^(6h) is a hydrogen atom, alkyl or haloalkyl;

R^(6k) is a hydrogen atom, alkyl or haloalkyl;

R^(6m) is each independently halogen, alkyl, haloalkyl, or

a group represented by the following formula: —OR^(6n), —C(═O)—OR^(6n),—SO₂R^(6n), or —N(R^(6n))(R^(6p)), ortwo of R^(6m) which are attached to the same carbon atom may be takentogether to form oxo,wherein R^(6n) is a hydrogen atom, alkyl or haloalkyl;

R^(6p) is a hydrogen atom, alkyl or haloalkyl;

f and k are each independently 0, 1, 2 or 3;

g is 1 or 2;

provided that the following compounds are excluded:

or a pharmaceutically acceptable salt thereof.

Herein, in the case that “two of R^(2e) which are attached to theadjacent carbon atoms and/or two of R^(2f) which are attached to theadjacent carbon atoms may be taken together to form a bond”, “two ofR^(3a) which are attached to the adjacent carbon atoms and/or two ofR^(3b) which are attached to the adjacent carbon atoms may be takentogether to form a bond”, “two of R^(3a) which are attached to theadjacent carbon atoms and/or two of R^(3b) which are attached to theadjacent carbon atoms may be taken together to form a bond”, “two ofR^(5e) which are attached to the adjacent carbon atoms and/or two ofR^(5f) which are attached to the adjacent carbon atoms may be takentogether to form a bond” and “two of R^(6e) which are attached to theadjacent carbon atoms and/or two of R^(6f) which are attached to theadjacent carbon atoms may be taken together to form a bond”,“—(C(R^(2e))(R^(2f)))_(c)—”, “—(C(R^(3a))(R^(3b)))_(r)-”,“—(C(R^(5e))(R^(5f)))_(e)—”, “—(C(R^(6e))(R^(6f)))_(f)-” and“—(C(R^(6e))(R^(6f)))_(g)-” do not form consecutive double bonds.

8) The compound according to 7),wherein —X— is —N(R³)— or —S—, ═Y— is ═CH—, and —Z— is —S—,or a pharmaceutically acceptable salt thereof.9) The compound according to any one of 7) or 8),wherein a is 0, 1 or 2,

b is 0, 1, 2 or 3, and

R^(2d) is each independently a hydrogen atom, halogen, alkyl, haloalkyl,or a group represented by the following formula: —OR^(2g),—O—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d), —C(═O)—R^(2g),—C(═O)—OR^(2g), —C(═O)—N(R^(2g))(R^(2h)),—C(═O)—N(R^(2g))—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d), —SO₂R^(2g),—SO₂-E-(R^(2k))_(d), —N(R^(2g))—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d),—N(R^(2g))—C(═O)—R^(2h), —N(R^(2g))—C(═O)-E-(R^(2k))_(d), or-E-(R^(2k))_(d),

wherein c is 0, 1 or 2,or a pharmaceutically acceptable salt thereof.10) The compound according to any one of 7) to 9),wherein R³ is a hydrogen atom or a group represented by the followingformula: -E-(R^(3c))_(d),wherein E is a benzene ring,or a pharmaceutically acceptable salt thereof.11) The compound according to any one of 7) to 10),wherein R⁵ is alkyl, or a group represented by the following formula:—(C(R^(5e))(R^(5f)))_(e)—OR^(5g),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—R^(5h)—(C(R^(5e))(R^(5f)))_(e)—O—C(═O)—N(R^(5g))(R^(5h)),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—N(R^(5h))(R^(5k)),—(C(R^(5e))(R^(5f)))_(e)—CN, —(C(R^(5e))(R^(5f)))_(e)-G-(R^(5m))_(h),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—OR^(5h),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)-G-(R^(5m))_(h), or—(C((R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—(CH₂)—OR^(5h),wherein G is a non-aromatic heterocycle; e is 1, 2 or 3,or a pharmaceutically acceptable salt thereof.12) The compound according to any one of 7) to 11),wherein R⁶ is alkyl, or a group represented by the following formula:—(C(R^(6e))(R^(6f)))_(f)—OR^(6g),—(C((R^(6e))(R^(6f)))_(g)—N(R^(6g))(R^(6h)), or —C(R^(6e))(R^(6f))—CN,

f is 0, 1 or 2,

or a pharmaceutically acceptable salt thereof.13) A pharmaceutical composition containing the compound according toany one of 1) to 12), or a pharmaceutically acceptable salt thereof.14) The pharmaceutical composition according to 13) for inhibiting aTRPV4 receptor.15) A method for treating or preventing a TRPV4 receptor-mediateddisorder, which comprises administering the compound according to anyone of 1) to 12), or a pharmaceutically acceptable salt thereof to asubject.16) The compound according to any one of 1) to 12), or apharmaceutically acceptable salt thereof for use in a method fortreating or preventing a TRPV4 receptor-mediated disorder.17) A pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound represented by formula (II):

wherein -L- is a group represented by the following formula: —N(R¹)—,—(CR^(1a)R^(1b))_(m)—N(R¹)—, —N(R¹)—C(═NR^(1c))—, —N(R¹)—C(═O)—,—N(R¹)—SO₂—, —(CR^(1a)R^(1b))_(m)—C(═O)—N(R¹)—, —SO₂—N(R¹)—, or—(CR^(1a)R^(1b))_(m)—O—,wherein R¹ is a hydrogen atom, substituted or unsubstituted alkyl,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, or substituted or unsubstituted non-aromaticheterocyclyl;

R^(1a) is each independently a hydrogen atom, halogen, hydroxy,sulfanyl, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substitutedor unsubstituted alkynylcarbonyl, substituted or unsubstituted amino,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkyloxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl,substituted or unsubstituted alkenylsulfanyl, substituted orunsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, substituted or unsubstituted non-aromaticheterocyclylsulfonyl,

R^(1a) and R^(1b) which are attached to the same carbon atom may betaken together to form oxo, substituted or unsubstituted imino, asubstituted or unsubstituted non-aromatic carbocycle or a substituted orunsubstituted non-aromatic heterocycle;

R^(1b) is each independently a hydrogen atom, halogen, hydroxy,sulfanyl, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substitutedor unsubstituted alkynylcarbonyl, substituted or unsubstituted amino,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkyloxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl,substituted or unsubstituted alkenylsulfanyl, substituted orunsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, substituted or unsubstituted non-aromaticheterocyclylsulfonyl,

R^(1a) and R^(1b) which are attached to the same carbon atom may betaken together to form oxo, substituted or unsubstituted imino, asubstituted or unsubstituted non-aromatic carbocycle or a substituted orunsubstituted non-aromatic heterocycle;

R^(1c) is a hydrogen atom, hydroxy, cyano, substituted or unsubstitutedalkyl, substituted or unsubstituted alkyloxy or substituted orunsubstituted amino

m is an integer from 0 to 3;

—X— is —N(R³)—, —O— or —S—;

═Y— is ═C(R⁴)— or ═N—;

—Z— is —N(R⁷)—, —O— or —S—;

═W— is ═C(R⁸)— or ═N—;

R² is substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted amino, substituted or unsubstituted imino,substituted or unsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy,substituted or unsubstituted non-aromatic carbocyclyloxy, substituted orunsubstituted aromatic heterocyclyloxy, substituted or unsubstitutednon-aromatic heterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, or substituted or unsubstituted non-aromaticheterocyclylsulfanyl, or

a group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c), wherein R^(2a) is each independently ahydrogen atom, halogen, hydroxy, carboxy, sulfanyl, cyano, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkyloxy, substituted or unsubstituted alkenyloxy, substituted orunsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl,substituted or unsubstituted alkenylcarbonyl, substituted orunsubstituted alkynylcarbonyl, substituted or unsubstituted amino,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;

R^(2b) is each independently a hydrogen atom, halogen, hydroxy, carboxy,sulfanyl, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substitutedor unsubstituted alkynylcarbonyl, substituted or unsubstituted amino,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;

R^(2a) and R^(2b) which are attached to the same carbon atom may betaken together to form oxo, substituted or unsubstituted imino, asubstituted or unsubstituted non-aromatic carbocycle, or a substitutedor unsubstituted non-aromatic heterocycle, two of R^(2a) which areattached to the adjacent carbon atoms and/or two of R^(2b) which areattached to the adjacent carbon atoms may be taken together to form abond;

R^(2c) is a hydrogen atom, halogen, hydroxy, carboxy, sulfanyl, sulfino,sulfo, cyano, hydrazino, ureido, amidino, guanidino, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkyloxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted orunsubstituted alkenylcarbonyl, substituted or unsubstitutedalkynylcarbonyl, substituted or unsubstituted amino, substituted orunsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted imino, substituted or unsubstituted imino,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted non-aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted aromaticheterocyclylcarbonyloxy, substituted or unsubstituted non-aromaticheterocyclylcarbonyloxy, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;

n is an integer from 1 to 3;

R³ and R⁷ are each independently a hydrogen atom, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkylsulfonyl,substituted or unsubstituted alkenylsulfonyl, substituted orunsubstituted alkynylsulfonyl, substituted or unsubstituted carbamoyl,or substituted or unsubstituted sulfamoyl, substituted or unsubstitutedaromatic carbocyclyl, substituted or unsubstituted non-aromaticcarbocyclyl, substituted or unsubstituted aromatic heterocyclyl, orsubstituted or unsubstituted non-aromatic heterocyclyl;

R⁴, R⁵ and R⁸ are each independently a hydrogen atom, halogen, hydroxy,carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, cyano, nitro,azido, amidino, guanidino, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, substituted or unsubstituted imino,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;

R⁶ is a hydrogen atom, halogen, hydroxy, formyl, formyloxy, sulfanyl,thioformyl, cyano, nitro, nitroso, azido, substituted or unsubstitutedamidino, substituted or unsubstituted guanidino, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkyloxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted orunsubstituted alkenylcarbonyl, substituted or unsubstitutedalkynylcarbonyl, substituted or unsubstituted amino, substituted orunsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;

provided thatwhen -L- is —N(R¹)—C(═O)—CH₂—,substituted or unsubstituted amino in R⁶ is an amino group representedby substituted or unsubstituted non-aromatic heterocyclyl,when -L- is —N(R¹)— or —N(R¹)—C(═O)—,a group represented by the following formula:

is none of groups represented by the following formula:

wherein R³ is a hydrogen atom, substituted or unsubstitutedalkylcarbonyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted aromatic carbocyclylcarbonyl, or substituted orunsubstituted aromatic heterocyclylcarbonyl;

R⁴ is

provided that the following compounds are excluded:

or a pharmaceutically acceptable salt thereof.Herein, in the case that “R^(2a) which are attached to the adjacentcarbon atoms and/or R^(2b) which are attached to the adjacent carbonatoms may be taken together to form a bond”, and “—(CR^(2a)R^(2b))_(n)—”do not form consecutive double bonds.18) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to 17), wherein a group represented bythe following formula:

is a group represented by the following formula:

wherein R⁴, R⁵, R⁶ and R⁷ are the same as the above 17); X1 is —N(R³)—or —S—; and R³ is the same as the above 17),or a pharmaceutically acceptable salt thereof.19) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to 17) or 18), wherein a grouprepresented by the following formula:

is a group represented by the following formula:

wherein R⁴, R⁵ and R⁶ are the same as the above 17); X1 is —N(R³)— or—S—; and R³ is the same as the above 17),or a pharmaceutically acceptable salt thereof.20) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 17) to 19),wherein -L- is —N(R¹)—, —N(R¹)—C(═O)—, —N(R¹)—SO₂—, —C(═O)—N(R¹)—,—C(R^(1a)R^(1b))—O— or —(CR^(1a)R^(1b))₂—O—;wherein R¹ is a hydrogen atom; R^(1a) is each independently a hydrogenatom, halogen, hydroxy, substituted or unsubstituted alkyl, orsubstituted or unsubstituted alkyloxy; and R^(1b) is each independentlya hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl,or substituted or unsubstituted alkyloxy,or a pharmaceutically acceptable salt thereof.21) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 17) to 20),wherein -L- is —N(R¹)—, —N(R¹)—C(═O)—, or —C(═O)—N(R¹)—,wherein R¹ is a hydrogen atom,or a pharmaceutically acceptable salt thereof.22) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 17) to 21),wherein R² is substituted or unsubstituted amino, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, ora group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c),wherein R^(2a) is each independently a hydrogen atom, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkyloxy, R^(2b) is each independently hydrogen atom, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkyloxy, orR^(2a) and R^(2b) may be taken together to form oxo, substituted orunsubstituted non-aromatic carbocyclyl, or substituted or unsubstitutednon-aromatic heterocyclyl;R^(2c) is substituted or unsubstituted aromatic carbocyclyl, substitutedor unsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy,substituted or unsubstituted non-aromatic carbocyclyloxy, substituted orunsubstituted aromatic heterocyclyloxy, substituted or unsubstitutednon-aromatic heterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylamino, substituted or unsubstituted non-aromaticcarbocyclylamino, substituted or unsubstituted aromaticheterocyclylamino, substituted or unsubstituted non-aromaticheterocyclylamino, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl; andn is an integer from 1 to 3;or a pharmaceutically acceptable salt thereof.23) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 17) to 22),wherein R² is substituted or unsubstituted aromatic carbocyclyl,substituted or unsubstituted non-aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic heterocyclyl, or a group represented by the followingformula: —(CR^(2a)R^(2b))_(n)—R^(2c)wherein R^(2a) is each independently a hydrogen atom, halogen,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy, R^(2b) is each independently hydrogen atom, halogen,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy, orR^(2a) and R^(2b) may be taken together to form substituted orunsubstituted non-aromatic carbocyclyl, or substituted or unsubstitutednon-aromatic heterocyclyl;R^(2c) is substituted or unsubstituted aromatic carbocyclyl, substitutedor unsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl; andn is an integer of 1,or a pharmaceutically acceptable salt thereof.24) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 17) to 23),wherein R³ is a hydrogen atom, substituted or unsubstituted alkyl,substituted or unsubstituted aromatic carbocyclyl or substituted orunsubstituted aromatic heterocyclyl,or a pharmaceutically acceptable salt thereof.25) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 17) to 24),wherein R⁴ is a hydrogen atom, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted aromatic carbocyclyl,substituted or unsubstituted non-aromatic carbocyclyl, or substituted orunsubstituted aromatic heterocyclyl,or a pharmaceutically acceptable salt thereof.26) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 17) to 25),wherein R⁵ is a hydrogen atom, halogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkylcarbonyl, substituted or unsubstitutedalkyloxycarbonyl, or substituted or unsubstituted carbamoyl,or a pharmaceutically acceptable salt thereof.27) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 17) to 26),wherein R⁶ is a hydrogen atom, halogen, hydroxy, amidino, guanidino,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkylcarbonyl, or substituted orunsubstituted carbamoyl,or a pharmaceutically acceptable salt thereof.28) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 17) to 27),wherein R⁷ is a hydrogen atom, substituted or unsubstituted alkyl,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, or substituted or unsubstituted non-aromaticheterocyclyl,or a pharmaceutically acceptable salt thereof.29) A method for treating or preventing a TRPV4 receptor-mediateddisorder, which comprises administering the pharmaceutical compositionfor inhibiting a TRPV4 receptor containing the compound according to anyone of 17) to 28), or a pharmaceutically acceptable salt thereof to asubject.30) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 17) to 28), or apharmaceutically acceptable salt thereof for use in a method fortreating or preventing a TRPV4 receptor-mediated disorder.

Furthermore, the present invention relates to the following 1′) to 18′).

1′) A compound represented by formula (I):

wherein R¹ is a hydrogen atom, substituted or unsubstituted alkyl,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, or substituted or unsubstituted non-aromaticheterocyclyl;

—X— is —N(R³)—, —O— or —S—;

═Y— is ═C(R⁴)— or ═N—;

—Z— is —N(R⁷)—, —O— or —S—;

R² is substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted amino, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, substituted orunsubstituted non-aromatic heterocyclyl, substituted or unsubstitutedaromatic carbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylsulfanyl, substituted orunsubstituted non-aromatic carbocyclylsulfanyl, substituted orunsubstituted aromatic heterocyclylsulfanyl, or substituted orunsubstituted non-aromatic heterocyclylsulfanyl, or

a group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein R^(2a) is each independently a hydrogen atom, halogen, hydroxy,carboxy, sulfanyl, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, substituted or unsubstitutedalkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy,substituted or unsubstituted alkynylcarbonyloxy, substituted orunsubstituted alkyloxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl,substituted or unsubstituted carbamoyl, substituted or unsubstitutedsulfamoyl, substituted or unsubstituted aromatic carbocyclyl,substituted or unsubstituted non-aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic heterocyclyl, substituted or unsubstituted aromaticcarbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylcarbonyl, substituted orunsubstituted non-aromatic carbocyclylcarbonyl, substituted orunsubstituted aromatic heterocyclylcarbonyl, substituted orunsubstituted non-aromatic heterocyclylcarbonyl, substituted orunsubstituted aromatic carbocyclyloxycarbonyl, substituted orunsubstituted non-aromatic carbocyclyloxycarbonyl, substituted orunsubstituted aromatic heterocyclyloxycarbonyl, substituted orunsubstituted non-aromatic heterocyclyloxycarbonyl, substituted orunsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstitutednon-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;R^(2b) is each independently a hydrogen atom, halogen, hydroxy, carboxy,sulfanyl, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substitutedor unsubstituted alkynylcarbonyl, substituted or unsubstituted amino,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;R^(2a) and R^(2b) which are attached to the same carbon atom may betaken together to form oxo, substituted or unsubstituted imino, asubstituted or unsubstituted non-aromatic carbocycle, or a substitutedor unsubstituted non-aromatic heterocycle, two of R^(2a) which areattached to the adjacent carbon atoms and/or two of R^(2b) which areattached to the adjacent carbon atoms may be taken together to form abond;R^(2c) is a hydrogen atom, halogen, hydroxy, carboxy, sulfanyl, sulfino,sulfo, cyano, hydrazino, ureido, amidino, guanidino, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkyloxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted orunsubstituted alkenylcarbonyl, substituted or unsubstitutedalkynylcarbonyl, substituted or unsubstituted amino, substituted orunsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted imino, substituted or unsubstitutedalkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy,substituted or unsubstituted alkynylcarbonyloxy, substituted orunsubstituted alkyloxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted carbamoyl, substituted or unsubstitutedsulfamoyl, substituted or unsubstituted aromatic carbocyclyl,substituted or unsubstituted non-aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic heterocyclyl, substituted or unsubstituted aromaticcarbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylcarbonyl, substituted orunsubstituted non-aromatic carbocyclylcarbonyl, substituted orunsubstituted aromatic heterocyclylcarbonyl, substituted orunsubstituted non-aromatic heterocyclylcarbonyl, substituted orunsubstituted aromatic carbocyclyloxycarbonyl, substituted orunsubstituted non-aromatic carbocyclyloxycarbonyl, substituted orunsubstituted aromatic heterocyclyloxycarbonyl, substituted orunsubstituted non-aromatic heterocyclyloxycarbonyl, substituted orunsubstituted aromatic carbocyclylcarbonyloxy, substituted orunsubstituted non-aromatic carbocyclylcarbonyloxy, substituted orunsubstituted aromatic heterocyclylcarbonyloxy, substituted orunsubstituted non-aromatic heterocyclylcarbonyloxy, substituted orunsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstitutednon-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;n is an integer from 1 to 3;

R³ and R⁷ are each independently a hydrogen atom, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkylsulfonyl,substituted or unsubstituted alkenylsulfonyl, substituted orunsubstituted alkynylsulfonyl, substituted or unsubstituted carbamoyl,substituted or unsubstituted sulfamoyl, substituted or unsubstitutedaromatic carbocyclyl, substituted or unsubstituted non-aromaticcarbocyclyl, substituted or unsubstituted aromatic heterocyclyl, orsubstituted or unsubstituted non-aromatic heterocyclyl;

R⁴ and R⁵ are each independently a hydrogen atom, halogen, hydroxy,carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, cyano, nitro,azido, amidino, guanidino, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, substituted or unsubstituted imino,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl; and

R⁶ is a hydrogen atom, halogen, hydroxy, formyl, formyloxy, sulfanyl,thioformyl, cyano, substituted or unsubstituted amidino, substituted orunsubstituted guanidino, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkyloxy, substituted or unsubstitutedalkenyloxy, substituted or unsubstituted alkynyloxy, substituted orunsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;

provided that the following compounds are excluded:

or a pharmaceutically acceptable salt thereof.2′) The compound according to 1′),wherein R¹ is a hydrogen atom,or a pharmaceutically acceptable salt thereof.3′) The compound according to 1′) or 2′),wherein —Z— is —O— or —S—,or a pharmaceutically acceptable salt thereof.4′) The compound according to any one of 1′) to 3′),wherein R² is substituted or unsubstituted amino, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, ora group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c),wherein R^(2a) is each independently a hydrogen atom, halogen, hydroxy,carboxy, sulfanyl, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted amino, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted non-aromatic carbocyclyl, or substituted or unsubstitutednon-aromatic heterocyclyl;R^(2b) is each independently a hydrogen atom, halogen, hydroxy, carboxy,sulfanyl, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedamino, substituted or unsubstituted alkylsulfanyl, substituted orunsubstituted alkenylsulfanyl, substituted or unsubstitutedalkynylsulfanyl, substituted or unsubstituted carbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted non-aromaticcarbocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl;R^(2a) and R^(2b) which are attached to the same carbon atom at any oneposition may be taken together to form oxo, substituted or unsubstitutedimino, a substituted or unsubstituted non-aromatic carbocycle, or asubstituted or unsubstituted non-aromatic heterocycle;R^(2c) is a hydrogen atom, halogen, hydroxy, carboxy, cyano, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedamino, substituted or unsubstituted alkylsulfonyl, substituted orunsubstituted alkenylsulfonyl, substituted or unsubstitutedalkynylsulfonyl, substituted or unsubstituted carbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, substituted orunsubstituted non-aromatic heterocyclyl, substituted or unsubstitutedaromatic carbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylsulfanyl, substituted orunsubstituted non-aromatic carbocyclylsulfanyl, substituted orunsubstituted aromatic heterocyclylsulfanyl, substituted orunsubstituted non-aromatic heterocyclylsulfanyl, substituted orunsubstituted non-aromatic carbocyclylsulfonyl, substituted orunsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstitutedaromatic heterocyclylsulfonyl, or substituted or unsubstitutednon-aromatic heterocyclylsulfonyl; andn is an integer from 1 to 3,or a pharmaceutically acceptable salt thereof.5′) The compound according to any one of 1′) to 4′),wherein R⁴ and R⁵ are each independently a hydrogen atom, halogen,cyano, substituted or unsubstituted alkyl, substituted or unsubstitutedamino, substituted or unsubstituted carbamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclylcarbonyl, substitutedor unsubstituted non-aromatic carbocyclylcarbonyl, substituted orunsubstituted aromatic heterocyclylcarbonyl, substituted orunsubstituted non-aromatic heterocyclylcarbonyl, substituted orunsubstituted aromatic carbocyclyloxycarbonyl, substituted orunsubstituted non-aromatic carbocyclyloxycarbonyl, substituted orunsubstituted aromatic heterocyclyloxycarbonyl, or substituted orunsubstituted non-aromatic heterocyclyloxycarbonyl,or a pharmaceutically acceptable salt thereof.6′) The compound according to any one of 1′) to 5′),wherein R⁶ is a hydrogen atom, halogen, hydroxy, carboxy, sulfanyl,sulfino, sulfo, cyano, substituted or unsubstituted amidino, substitutedor unsubstituted guanidino, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkyloxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl,substituted or unsubstituted alkenylsulfanyl, substituted orunsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, or substituted or unsubstituted sulfamoyl,or a pharmaceutically acceptable salt thereof.7′) A pharmaceutical composition containing the compound according toany one of 1′) to 6′), or a pharmaceutically acceptable salt thereof.8′) The pharmaceutical composition according to 7′) for inhibiting aTRPV4 receptor.9′) A method for treating or preventing a TRPV4 receptor-mediateddisorder, which comprises administering the compound according to anyone of 1′) to 6′), or a pharmaceutically acceptable salt thereof to asubject.10′) The compound according to any one of 1′) to 6′), or apharmaceutically acceptable salt thereof for use in a method fortreating or preventing a TRPV4 receptor-mediated disorder.11′) A pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound represented by formula (II):

wherein -L- is a group represented by the following formula: —N(R¹)—,—(CR^(1a)R^(1b))_(m)—N(R¹)—, —N(R¹)—C(═O)—, —N(R¹)—SO₂,—(CR^(1a)R^(1b))_(m)—C(═O)—N(R¹)—, —SO₂—N(R¹)— or—(CR^(1a)R^(1b))_(m)—O—,wherein R¹ is a hydrogen atom, substituted or unsubstituted alkyl,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, or substituted or unsubstituted non-aromaticheterocyclyl;R^(1a) is each independently a hydrogen atom, halogen, hydroxy,sulfanyl, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substitutedor unsubstituted alkynylcarbonyl, substituted or unsubstituted amino,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkyloxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl,substituted or unsubstituted alkenylsulfanyl, substituted orunsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, substituted or unsubstituted non-aromaticheterocyclylsulfonyl,R^(1a) and R^(1b) which are attached to the same carbon atom may betaken together to form oxo, substituted or unsubstituted imino, asubstituted or unsubstituted non-aromatic carbocycle or a substituted orunsubstituted non-aromatic heterocycle;R^(1b) is each independently a hydrogen atom, halogen, hydroxy,sulfanyl, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substitutedor unsubstituted alkynylcarbonyl, substituted or unsubstituted amino,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkyloxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl,substituted or unsubstituted alkenylsulfanyl, substituted orunsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, substituted or unsubstituted non-aromaticheterocyclylsulfonyl,R^(1a) and R^(1b) which are attached to the same carbon atom may betaken together to form oxo, substituted or unsubstituted imino, asubstituted or unsubstituted non-aromatic carbocycle or a substituted orunsubstituted non-aromatic heterocycle; m is an integer from 0 to 3;

—X— is —N(R³)—, —O— or —S—;

═Y— is ═C(R⁴)— or ═N—;

—Z— is —N(R⁷)—, —O— or —S—;

═W— is ═C(R⁸)— or ═N—;

R² is substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted amino, substituted or unsubstituted imino,substituted or unsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy,substituted or unsubstituted non-aromatic carbocyclyloxy, substituted orunsubstituted aromatic heterocyclyloxy, substituted or unsubstitutednon-aromatic heterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, or substituted or unsubstituted non-aromaticheterocyclylsulfanyl, or

a group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein R^(2a) is each independently a hydrogen atom, halogen, hydroxy,carboxy, sulfanyl, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, substituted or unsubstitutedalkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy,substituted or unsubstituted alkynylcarbonyloxy, substituted orunsubstituted alkyloxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl,substituted or unsubstituted carbamoyl, substituted or unsubstitutedsulfamoyl, substituted or unsubstituted aromatic carbocyclyl,substituted or unsubstituted non-aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic heterocyclyl, substituted or unsubstituted aromaticcarbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylcarbonyl, substituted orunsubstituted non-aromatic carbocyclylcarbonyl, substituted orunsubstituted aromatic heterocyclylcarbonyl, substituted orunsubstituted non-aromatic heterocyclylcarbonyl, substituted orunsubstituted aromatic carbocyclyloxycarbonyl, substituted orunsubstituted non-aromatic carbocyclyloxycarbonyl, substituted orunsubstituted aromatic heterocyclyloxycarbonyl, substituted orunsubstituted non-aromatic heterocyclyloxycarbonyl, substituted orunsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstitutednon-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;R^(2b) is each independently a hydrogen atom, halogen, hydroxy, carboxy,sulfanyl, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substitutedor unsubstituted alkynylcarbonyl, substituted or unsubstituted amino,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;R^(2a) and R^(2b) which are attached to the same carbon atom may betaken together to form oxo, substituted or unsubstituted imino, asubstituted or unsubstituted non-aromatic carbocycle, or a substitutedor unsubstituted non-aromatic heterocycle, two of R^(2a) which areattached to the adjacent carbon atoms and/or two of R^(2b) which areattached to the adjacent carbon atoms may be taken together to form abond;R^(2c) is a hydrogen atom, halogen, hydroxy, carboxy, sulfanyl, sulfino,sulfo, cyano, hydrazino, ureido, amidino, guanidino, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkyloxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted orunsubstituted alkenylcarbonyl, substituted or unsubstitutedalkynylcarbonyl, substituted or unsubstituted amino, substituted orunsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted imino, substituted or unsubstituted imino,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted non-aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted aromaticheterocyclylcarbonyloxy, substituted or unsubstituted non-aromaticheterocyclylcarbonyloxy, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;n is an integer from 1 to 3;

R³ and R⁷ are each independently a hydrogen atom, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkylsulfonyl,substituted or unsubstituted alkenylsulfonyl, substituted orunsubstituted alkynylsulfonyl, substituted or unsubstituted carbamoyl,or substituted or unsubstituted sulfamoyl, substituted or unsubstitutedaromatic carbocyclyl, substituted or unsubstituted non-aromaticcarbocyclyl, substituted or unsubstituted aromatic heterocyclyl, orsubstituted or unsubstituted non-aromatic heterocyclyl;

R⁴, R⁵ and R⁸ are each independently a hydrogen atom, halogen, hydroxy,carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, cyano, nitro,azido, amidino, guanidino, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, substituted or unsubstituted imino,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;

R⁶ is a hydrogen atom, halogen, hydroxy, formyl, formyloxy, sulfanyl,thioformyl, cyano, nitro, nitroso, azido, substituted or unsubstitutedamidino, substituted or unsubstituted guanidino, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkyloxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted orunsubstituted alkenylcarbonyl, substituted or unsubstitutedalkynylcarbonyl, substituted or unsubstituted amino, substituted orunsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;

provided thatwhen -L- is —N(R¹)C(═O)—CH₂—,substituted or unsubstituted amino in R⁶ is an amino group representedby substituted or unsubstituted non-aromatic heterocyclyl,when -L- is —N(R¹)—,a group represented by the following formula:

is none of groups represented by the following formula:

wherein R³ is a hydrogen atom, substituted or unsubstitutedalkylcarbonyl, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl;provided that the following compounds are excluded:

or a pharmaceutically acceptable salt thereof.12′) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to 11′), wherein a group represented bythe following formula:

is a group represented by the following formula:

wherein R⁴, R⁵, R⁶ and R⁷ are the same as the above 11′); and X1 is —O—or —S—,or a pharmaceutically acceptable salt thereof.13′) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to 11′) or 12′),wherein -L- is —N(R¹)—, —N(R¹)—C(═O)—, —N(R¹)—SO₂—,—C(R^(1a)R^(1b))—C(═O)—N(R¹)—, —C(R^(1a)R^(1b))—O— or—(CR^(1a)R^(1b))₂—O—;wherein R¹ is a hydrogen atom; R^(1a) is each independently a hydrogenatom, halogen, hydroxy, substituted or unsubstituted alkyl, orsubstituted or unsubstituted alkyloxy;R^(1b) is each independently hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy,or a pharmaceutically acceptable salt thereof.14′) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 11′) to 13′),R² is substituted or unsubstituted amino, substituted or unsubstitutedaromatic carbocyclyl, substituted or unsubstituted non-aromaticcarbocyclyl, substituted or unsubstituted aromatic heterocyclyl,substituted or unsubstituted non-aromatic heterocyclyl, ora group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c),wherein R^(2a) is each independently a hydrogen atom, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkyloxy, orR^(2a) and R^(2b) may be taken together to form oxo, substituted orunsubstituted non-aromatic carbocyclyl, or substituted or unsubstitutednon-aromatic heterocyclyl;R^(2c) is substituted or unsubstituted aromatic carbocyclyl, substitutedor unsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy,substituted or unsubstituted non-aromatic carbocyclyloxy, substituted orunsubstituted aromatic heterocyclyloxy, substituted or unsubstitutednon-aromatic heterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylamino, substituted or unsubstituted non-aromaticcarbocyclylamino, substituted or unsubstituted aromaticheterocyclylamino, substituted or unsubstituted non-aromaticheterocyclylamino, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;R^(2b) is each independently a hydrogen atom, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkyloxy, orR^(2a) and R^(2b) may be taken together to form oxo, substituted orunsubstituted non-aromatic carbocyclyl, or substituted or unsubstitutednon-aromatic heterocyclyl;R^(2c) is substituted or unsubstituted aromatic carbocyclyl, substitutedor unsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy,substituted or unsubstituted non-aromatic carbocyclyloxy, substituted orunsubstituted aromatic heterocyclyloxy, substituted or unsubstitutednon-aromatic heterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylamino, substituted or unsubstituted non-aromaticcarbocyclylamino, substituted or unsubstituted aromaticheterocyclylamino, substituted or unsubstituted non-aromaticheterocyclylamino, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;n is an integer from 1 to 3,or a pharmaceutically acceptable salt thereof.15′) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 11′) to 14′),R⁴ is a hydrogen atom, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted carbamoyl,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, or substituted or unsubstitutedaromatic heterocyclyl,or a pharmaceutically acceptable salt thereof.16′) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 11′) to 15′),R⁵ is a hydrogen atom, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, orsubstituted or unsubstituted carbamoyl,or a pharmaceutically acceptable salt thereof.17′) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 11′) to 16′),R⁶ is a hydrogen atom, halogen, hydroxy, amidino, guanidino, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkylcarbonyl, or substituted orunsubstituted carbamoyl,or a pharmaceutically acceptable salt thereof.18′) The pharmaceutical composition for inhibiting a TRPV4 receptorcontaining a compound according to any one of 11′) to 17′),R⁷ is a hydrogen atom, substituted or unsubstituted alkyl, substitutedor unsubstituted carbamoyl, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, or substituted orunsubstituted non-aromatic heterocyclyl,or a pharmaceutically acceptable salt thereof.

EFFECT OF THE INVENTION

The present invention provides a compound useful in the treatment and/orprevention of a TRPV4 receptor-mediated disorder, or a pharmaceuticallyacceptable salt thereof. The compound of the present invention shows anexcellent TRPV4 inhibitory activity as described in test examples below.Thus, a pharmaceutical composition of the present invention is availablefor therapeutic agent and/or prophylactic agent for inflammatory pain(bladder inflammatory pain, pain after tooth extraction, postoperativepain, pain in the low back, periarthritis scapulohumeralis,cervico-omo-brachial syndrome, inflammation of a tendon or a tendonsheath, osteoarthritis, chronic articular rheumatism), neuropathic pain(sciatica, postherpetic neuralgia, diabetic neuropathy), pain related tocancer (cancer pain, bone metastasis pain, pain with the administrationof anticancer agent), IBS, inflammatory bowel disease, osteoporosis,articular cartilage degeneration, cerebral stroke, incontinence,overactive bladder, urinary disturbance by bladder inflammation, asthma,dry skin, atopic dermatitis, metastasis and invasion of cancer, cornealulcer, obesity, insulin resistance, diabetes, or the like.

The compound of the present invention is a compound having utility as amedicament. Herein, utility as a medicament includes the followingpoints: the compound has good metabolic stability; the induction of adrug-metabolizing enzyme is low; the inhibition of a drug-metabolizingenzyme which metabolizes another drug is low; the compound has high oralabsorbency; the inhibition of hERG is low; the clearance is low; and/orthe half-life is sufficiently long to express the efficacy; or the like.

MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention is described with reference toembodiments. It should be understood that, throughout the presentspecification, the expression of a singular form includes the concept ofits plural form unless specified otherwise. Accordingly, it should beunderstood that an article in singular form (for example, in the Englishlanguage, “a,” “an,” “the,” and the like) includes the concept of itsplural form unless specified otherwise. Furthermore, it should beunderstood that the terms used herein are used in a meaning normallyused in the art unless specified otherwise. Thus, unless definedotherwise, all technical and scientific terms used herein have the samemeaning as those generally understood by those skilled in the art in thefield to which the present invention pertains. If there is acontradiction, the present specification (including definitions)precedes.

Terms used in the present specification are explained below. In thepresent specification, each term is used in an unequivocal meaning, andhas the same meaning when it is used alone or together with other terms.

“Halogen” includes a fluorine atom, chlorine atom, bromine atom andiodine atom. For example, it includes a fluorine atom, chlorine atom andbromine atom.

“Alkyl” includes a C1 to C10 linear or branched hydrocarbon group. Forexample, it includes methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl,n-decyl and the like.

An embodiment of “alkyl” is C1-C6 alkyl. Another embodiment is C1-C4alkyl. When the carbon number is specified in particular, an “alkyl” hascarbon in a range of the number.

“Alkenyl” includes a C2 to C10 linear or branched hydrocarbon grouphaving one or more double bond(s) at any position(s). For example, itincludes vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl,prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl,isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl,dodecenyl, tridecenyl, tetradecenyl, pentadecenyl and the like.

An embodiment of “alkenyl” is C2-C6 alkenyl. Another embodiment of“alkenyl” is C2-C4 alkenyl.

“Alkynyl” includes a C2 to C10 linear or branched hydrocarbon grouphaving one or more triple bond(s) at any position(s). For example, itincludes ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl,octynyl, nonynyl, decynyl and the like.

An embodiment of “alkynyl” is C2-C6 alkynyl. Another embodiment of“alkynyl” is C2-C4 alkynyl.

“Hydroxyalkyl” means a group wherein one or more hydrogen atom(s)attached to a carbon atom of the above “alkyl” is replaced with hydroxylgroup. For example, it includes hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-dihydroxyethyl andthe like.

An embodiment of “hydroxyalkyl” is hydroxymethyl.

“Aminoalkyl” means a group wherein one or more hydrogen atom(s) attachedto a carbon atom of the above “alkyl” is replaced with an amino group.For example, it includes aminomethyl, aminoethyl and the like.

“Alkylamino” means a group wherein one or two hydrogen atom(s) attachedto a nitrogen atom of an amino group is replaced with the above “alkyl”.For example, it includes methylamino, ethylamino, isopropylamino,dimethylamino, diethylamino, N,N-diisopropylamino,N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like.

“Alkylaminoalkyl” means a group wherein the above “alkylamino” is bondedto the above “alkyl”. For example, it includes dimethylaminomethyl,dimethylaminoethyl and the like.

“Alkyloxyalkyl” means a group wherein the above “alkyloxy” is bonded tothe above “alkyl”. For example, it includes methoxymethyl, methoxyethyl,ethoxymethyl and the like.

“Alkyloxyalkyloxy” means a group wherein the above “alkyloxy” is bondedto the above “alkyloxy”. For example, it includes methoxymethoxy,methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.

“Alkyloxy” includes a group wherein the above “alkyl” is bonded tooxygen atom. For example, it includes methoxy, ethoxy, n-propyloxy,isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy,pentyloxy, isopentyloxy, hexyloxy and the like.

An embodiment of “alkyloxy” includes C1-C6 alkyloxy. Another embodimentof “alkyloxy” includes C1-C4 alkyloxy. When the carbon number isspecified in particular, an “alkyloxy” has carbon in a range of thenumber.

“Alkenyloxy” includes a group wherein the above “alkenyl” is bonded tooxygen atom. For example, it includes vinyloxy, allyloxy, 1-propenyloxy,2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxyand the like.

“Alkynyloxy” includes a group wherein the above “alkynyl” is bonded tooxygen atom. For example, it includes ethynyloxy, 1-propynyloxy,2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy,2-octynyloxy and the like.

“Alkylcarbonyl” includes a group wherein the above “alkyl” is bonded tocarbonyl group. For example, it includes methylcarbonyl, ethylcarbonyl,n-propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl,isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl,hexylcarbonyl and the like. An embodiment of “alkylcarbonyl” is C1-C6alkylcarbonyl.

“Alkenylcarbonyl” includes a group wherein the above “alkenyl” is bondedto carbonyl group. For example, it includes ethylenylcarbonyl,propenylcarbonyl, butenylcarbonyl and the like.

“Alkynylcarbonyl” includes a group wherein the above “alkynyl” is bondedto carbonyl group. For example, it includes ethynylcarbonyl,propynylcarbonyl, butynylcarbonyl and the like.

“Alkylsulfonyl” includes a group wherein the above “alkyl” is bonded tosulfonyl group. For example, it includes methyl sulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butyl sulfonyl,isobutyl sulfonyl, sec-butyl sulfonyl, tert-butyl sulfonyl,n-pentylsulfonyl, isopentylsulfonyl, 2-pentylsulfonyl, 3-pentylsulfonyl,n-hexylsulfonyl, isohexylsulfonyl, 2-hexylsulfonyl, 3-hexylsulfonyl,n-heptylsulfonyl, n-octylsulfonyl and the like.

An embodiment of “alkylsulfonyl” is C1-C6 alkylsulfonyl. Anotherembodiment of is C1-C4 alkylsulfonyl.

“Alkenylsulfonyl” includes a group wherein the above “alkenyl” is bondedto sulfonyl group. For example, it includes ethylenylsulfonyl,propenylsulfonyl, butenylsulfonyl and the like.

“Alkynylsulfonyl” includes a group wherein the above “alkynyl” is bondedto sulfonyl group. For example, it includes ethynylsulfonyl,propynylsulfonyl, butynylsulfonyl and the like.

“Alkylcarbonyloxy” includes a group wherein the above “alkylcarbonyl” isbonded to oxygen atom. For example, it includes methylcarbonyloxy,ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy,tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and thelike.

An embodiment of “alkylcarbonyloxy” is C1-C6 alkylcarbonyloxy.

“Alkenylcarbonyloxy” includes a group wherein the above“alkenylcarbonyl” is bonded to oxygen atom. For example, it includesethylenylcarbonyloxy, propenylcarbonyloxy and the like.

“Alkynylcarbonyloxy” includes a group wherein the above“alkynylcarbonyl” is bonded to oxygen atom. For example, it includesethynylcarbonyloxy, propynylcarbonyloxy and the like.

“Alkyloxycarbonyl” includes a group wherein the above “alkyloxy” isbonded to carbonyl group. For example, it includes methyloxycarbonyl,ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl,n-butyloxycarbonyl, tert-butyloxycarbonyl, n-pentyloxycarbonyl and thelike.

An embodiment of “alkyloxycarbonyl” is C1-C6 alkyloxy. Anotherembodiment of “alkyloxycarbonyl” is C1-C4 alkyloxycarbonyl. Anotherembodiment of “alkyloxycarbonyl” is C1-C2 alkyloxycarbonyl.

“Alkenyloxycarbonyl” includes a group wherein the above “alkenyloxy” isbonded to carbonyl group. For example, it includes ethylenyloxycarbonyl,propenyloxycarbonyl, butenyloxycarbonyl and the like.

“Alkynyloxycarbonyl” includes a group wherein the above “alkynyloxy” isbonded to carbonyl group. For example, it includes ethynyloxycarbonyl,propynyloxycarbonyl, butynyloxycarbonyl and the like.

“Alkylsulfanyl” includes a group wherein a hydrogen atom bonded to asulfur atom of sulfanyl group is replaced with the above “alkyl”. Forexample, it includes methylsulfanyl, ethylsulfanyl, n-propylsulfanyl,isopropylsulfanyl, tert-butylsulfanyl, isobutylsulfanyl and the like.

“Alkenylsulfanyl” includes a group wherein a hydrogen atom bonded to asulfur atom of sulfanyl group is replaced with the above “alkenyl”. Forexample, it includes ethylenylsulfanyl, propenylsulfanyl,butenylsulfanyl and the like.

“Alkynylsulfanyl” includes a group wherein a hydrogen atom bonded to asulfur atom of sulfanyl group is replaced with the above “alkynyl”. Forexample, it includes ethynylsulfanyl, propynylsulfanyl, butynylsulfanyland the like.

“Alkylsulfinyl” includes a group wherein the above “alkyl” is bonded tosulfinyl group. For example, it includes methylsulfinyl, ethylsulfinyl,n-propylsulfinyl, isopropylsulfinyl and the like.

“Alkenylsulfinyl” includes a group wherein the above “alkenyl” is bondedto sulfinyl group. For example, it includes ethylenylsulfinyl,propenylsulfinyl, butenylsulfinyl and the like.

“Alkynylsulfinyl” includes a group wherein the above “alkynyl” is bondedto sulfinyl group. For example, it includes ethynylsulfinyl,propynylsulfinyl, butynylsulfinyl and the like.

“Alkylcarbamoyl” means a group wherein one or two hydrogen atom(s)attached to a nitrogen atom of carbamoyl group is replaced with theabove “alkyl”. When two hydrogen atoms are replaced with two alkylgroup, two alkyl group may be the same or different. For example, itincludes methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,diethylcarbamoyl, N-methyl-N-ethylcarbamoyl and the like.

“Hydroxyalkylcarbamoyl” means a group wherein one or two hydrogenatom(s) attached to a nitrogen atom of carbamoyl group is replaced withthe above “hydroxyalkyl”. When two hydrogen atoms are replaced with twohydroxyalkyl group, two hydroxyalkyl group may be the same or different.For example, it includes hydroxy ethylcarbamoyl and the like.

“Haloalkyl” includes a group wherein one or more hydrogen atom(s)attached to a carbon atom of the above “alkyl” is replaced with theabove “halogen”. For example, it includes monofluoromethyl,monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl,monochloromethyl, trifluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,2-dibromoethyl,1,1,1-trifluoropropane-2-yl and the like.

An embodiment of “haloalkyl” is trifluoromethyl, and trichloromethyl.

“Haloalkyloxy” means a group wherein the above “haloalkyl” is bonded tooxygen atom. For example, it includes monofluoromethoxy,monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy,trichloroethoxy and the like.

An embodiment of “haloalkyloxy” is trifluoromethoxy, andtrichloromethoxy.

“Haloalkylsulfonyl” includes a group wherein the above “haloalkyl” isbonded to sulfonyl group. For example, it includes monofluoromethylsulfonyl, monofluoroethyl sulfonyl, difluoromethyl sulfonyl,difluoroethyl sulfonyl, trifluoromethyl sulfonyl, trichloromethylsulfonyl and the like.

An embodiment of “haloalkylsulfonyl” is monofluoromethyl sulfonyl,difluoromethyl sulfonyl, difluoroethyl sulfonyl, and trifluoromethylsulfonyl.

An embodiment of “haloalkylcarbonyl” includes a group wherein the above“haloalkyl” is bonded to carbonyl group. For example, it includesmonofluoromethylcarbonyl, monofluoroethylcarbonyl,difluoromethylcarbonyl, difluoroethylcarbonyl, trifluoromethylcarbonyl,trichloromethylcarbonyl and the like.

An embodiment of “haloalkylcarbonyl” is monofluoromethylcarbonyl,difluoromethylcarbonyl, difluoroethylcarbonyl, trifluoromethylcarbonyl.

“Haloalkenyl”, “haloalkynyl”, “haloalkenyloxy”, “haloalkynyloxy”,“haloalkenylsulfonyl”, “haloalkynylsulfonyl”, “haloalkenylcarbonyl”,“haloalkynylcarbonyl”, “haloalkyloxyalkyl”, or “haloalkylcarbamoyl” meana group wherein one or more the above “halogen” is bonded to the “alkyl”part of the above “alkenyl”, the above “alkynyl”, the above“alkenyloxy”, the above “alkynyloxy”, the above “alkenylsulfonyl”, theabove “alkynylsulfonyl”, the above “alkenylcarbonyl”, the above“alkynylcarbonyl”, the above “alkyloxyalkyl” or “alkylcarbamoyl”,respectively.

“Aromatic carbocyclyl” includes a cyclic aromatic hydrocarbon groupwhich is monocyclic or polycyclic having two or more rings. For example,it includes benzene ring, naphthalene ring, anthracene ring,phenanthrene ring and the like.

An embodiment of “aromatic carbocyclyl” includes benzene ring andnaphthalene ring.

“Non-aromatic carbocyclyl” includes a cyclic saturated hydrocarbon groupor a cyclic unsaturated non-aromatic hydrocarbon group, which ismonocyclic or polycyclic having two or more rings. “Non-aromaticcarbocyclyl”, which is polycyclic having two or more rings, includes afused ring group wherein a non-aromatic carbocyclyl, which is monocyclicor polycyclic having two or more rings, is fused with a ring of theabove “aromatic carbocyclyl”.

In addition, the “non-aromatic carbocyclyl” also includes a group havinga bridge or a group to form a spiro ring as follows:

An embodiment of non-aromatic carbocyclyl which is monocyclic is C3 toC16, another embodiment is C3 to C12, and another embodiment is C3 toC8. For example, it includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclohexadienyl and the like.

A non-aromatic carbocyclyl which is polycyclic having two or more ringsincludes, for example, indanyl, indenyl, acenaphthyl,tetrahydronaphthyl, fluorenyl and the like.

“Aromatic heterocyclyl” includes an aromatic cyclyl, which is monocyclicor polycyclic having two or more rings, containing one or more, same ordifferent of heteroatom(s) selected independently from oxygen atom,sulfur atom and nitrogen atom.

“Aromatic heterocyclyl”, which is polycyclic having two or more rings,includes a fused ring group wherein an aromatic heterocyclyl, which ismonocyclic or polycyclic having two or more rings, is fused with a ringof the above “aromatic carbocyclyl”.

An embodiment of aromatic heterocyclyl which is monocyclic is 5- to8-membered, and another embodiment is 5- or 6-membered. For example, itincludes pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl,thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl,thiadiazolyl and the like.

An aromatic heterocyclyl which is bicyclic includes, for example,indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl,cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl,purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl,benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl,triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl,thiazolopyridyl and the like.

An aromatic heterocyclyl which is polycyclic having three or more ringsincludes, for example, carbazolyl, acridinyl, xanthenyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, dibenzofuryl and the like.

“Non-aromatic heterocyclyl” includes a non-aromatic carbocyclyl, whichis monocyclic or polycyclic having two or more rings, containing one ormore, same or different of heteroatom(s) selected independently fromoxygen atom, sulfur atom and nitrogen atom.

“Non-aromatic heterocyclyl”, which is polycyclic having two or morerings, includes a fused ring group wherein a non-aromatic heterocycle,which is monocyclic or polycyclic having two or more rings, is fusedwith a ring of the above “aromatic carbocyclyl”, “non-aromaticcarbocyclyl” and/or “aromatic heterocyclyl”.

In addition, the “non-aromatic heterocyclyl” also includes a grouphaving a bridge or a group to form a spiro ring as follows:

An embodiment of non-aromatic heterocyclyl which is monocyclic is 3- to8-membered, and another embodiment is 5- or 6-membered.

For example, it includes dioxanyl, thiiranyl, oxiranyl, oxetanyl,oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl,pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperidinyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl,thiomorpholino, dihydropyridinyl, tetrahydropyridinyl, tetrahydrofuryl,tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl,tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl,tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl,dioxolanyl, dioxazinyl, aziridinyl, dioxolinyl, oxepanyl, thiolanyl,thiinyl, thiazinyl and the like.

A non-aromatic heterocyclyl which is polycyclic having two or more ringsincludes, for example, indolinyl, isoindolinyl, chromanyl, isochromanyland the like.

The alkyl part of “aromatic carbocyclylalkyl”, “non-aromaticcarbocyclylalkyl”, “aromatic heterocyclylalkyl”, or “non-aromaticheterocyclylalkyl”, “aromatic carbocyclylalkyloxy”, “non-aromaticcarbocyclylalkyloxy”, “aromatic heterocyclylalkyloxy”, or “non-aromaticheterocyclylalkyloxy”, “aromatic carbocyclylalkyloxycarbonyl”,“non-aromatic carbocyclylalkyloxycarbonyl”, “aromaticheterocyclylalkyloxycarbonyl”, and “non-aromaticheterocyclylalkyloxycarbonyl”, or “aromatic carbocyclylalkyloxyalkyl”,“non-aromatic carbocyclylalkyloxyalkyl”, “aromaticheterocyclylalkyloxyalkyl”, or “non-aromatic heterocyclylalkyloxyalkyl”is also the same as the above “alkyl”.

“Aromatic carbocyclylalkyl” means an alkyl substituted with one or more“aromatic carbocyclyl” described above. For example, it includes benzyl,phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl, a group ofthe formula of

and the like.

An embodiment of “aromatic carbocyclylalkyl” is benzyl, phenethyl orbenzhydryl.

“Non-aromatic carbocyclylalkyl” means an alkyl substituted with one ormore “non-aromatic carbocyclyl” described above. “Non-aromaticcarbocyclylalkyl” also includes “non-aromatic carbocyclylalkyl” whereinthe alkyl part is substituted with the above “aromatic carbocyclyl”. Forexample, it includes cyclopropylmethyl, cyclobutylmethyl,cyclopenthylmethyl, cyclohexylmethyl, a group of the formula of

and the like.

“Aromatic heterocyclylalkyl” means an alkyl substituted with one or more“aromatic heterocyclyl” described above. “Aromatic heterocyclylalkyl”also includes “aromatic heterocyclylalkyl” wherein the alkyl part issubstituted with the above “aromatic carbocyclyl” and/or “non-aromaticcarbocyclyl”. For example, it includes pyridylmethyl, furanylmethyl,imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl,isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl,isopyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl, groups ofthe formula of

and the like.

“Non-aromatic heterocyclylalkyl” means an alkyl substituted with one ormore “non-aromatic heterocyclyl” described above. “Non-aromaticheterocyclylalkyl” also includes “non-aromatic heterocyclylalkyl”wherein the alkyl part is substituted with the above “aromaticcarbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”.For example, it includes tetrahydropyranylmethyl, morpholinylmethyl,morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups of theformula of

and the like.

“Aromatic carbocyclylalkyloxy” means an alkyloxy substituted with one ormore “aromatic carbocyclyl” described above. For example, it includesbenzyloxy, phenethyloxy, phenylpropyloxy, benzhydryloxy, trityloxy,naphthylmethyloxy, a group of the formula of

and the like.

“Non-aromatic carbocyclylalkyloxy” means an alkyloxy substituted withone or more “non-aromatic carbocyclyl” described above. “Non-aromaticcarbocyclylalkyloxy” also includes “non-aromatic carbocyclylalkyloxy”wherein the alkyl part is substituted with the above “aromaticcarbocyclyl”. For example, it includes cyclopropylmethyloxy,cyclobutylmethyloxy, cyclopenthylmethyloxy, cyclohexylmethyloxy, a groupof the formula of

and the like.

“Aromatic heterocyclylalkyloxy” means an alkyloxy substituted with oneor more “aromatic heterocyclyl” described above. “Aromaticheterocyclylalkyloxy” also includes “aromatic heterocyclylalkyloxy”wherein the alkyl part is substituted with the above “aromaticcarbocyclyl” and/or “non-aromatic carbocyclyl”. For example, it includespyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy,indolylmethyloxy, benzothiophenylmethyloxy, oxazolylmethyloxy,isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy,pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy,benzoxazolylmethyloxy, groups of the formula of

and the like.

“Non-aromatic heterocyclylalkyloxy” means an alkyloxy substituted withone or more “non-aromatic heterocyclyl” described above. “Non-aromaticheterocyclylalkyloxy” also includes “non-aromatic heterocyclylalkyloxy”wherein the alkyl part is substituted with the above “aromaticcarbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”.For example, it includes tetrahydropyranylmethyloxy,morpholinylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy,piperazinylmethyloxy, groups of the formula of

and the like.

“Aromatic carbocyclylalkyloxycarbonyl” means an alkyloxycarbonylsubstituted with one or more “aromatic carbocyclyl” described above. Forexample, it includes benzyloxycarbonyl, phenethyloxycarbonyl,phenylpropyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl,naphthylmethyloxycarbonyl, a group of the formula of

and the like.

“Non-aromatic carbocyclylalkyloxycarbonyl” means an alkyloxycarbonylsubstituted with one or more “non-aromatic carbocyclyl” described above.“Non-aromatic carbocyclylalkyloxycarbonyl” also includes “non-aromaticcarbocyclylalkyloxycarbonyl” wherein the alkyl part is substituted withthe above “aromatic carbocyclyl”. For example, it includescyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl,cyclopenthylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, a group ofthe formula of

and the like.

“Aromatic heterocyclylalkyloxycarbonyl” means an alkyloxycarbonylsubstituted with one or more “aromatic heterocyclyl” described above.“Aromatic heterocyclylalkyloxycarbonyl” also include “aromaticheterocyclylalkyloxycarbonyl” wherein the alkyl part is substituted withthe above “aromatic carbocyclyl” and/or “non-aromatic carbocyclyl”. Forexample, it includes pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl,imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl,benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl,isoxazolylmethyloxycarbonyl, thiazolylmethyloxycarbonyl,isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl,isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl,benzoxazolylmethyloxycarbonyl, groups of the formula of

and the like.

“Non-aromatic heterocyclylalkyloxycarbonyl” means an alkyloxycarbonylsubstituted with one or more “non-aromatic heterocyclyl” describedabove. “Non-aromatic heterocyclylalkyloxycarbonyl” also includes“non-aromatic heterocyclylalkyloxycarbonyl” wherein the alkyl part issubstituted with the above “aromatic carbocyclyl”, “non-aromaticcarbocyclyl” and/or “aromatic heterocyclyl”. For example, it includestetrahydropyranylmethyloxy, morpholinylmethyloxycarbonyl,morpholinylethyloxycarbonyl, piperidinylmethyloxycarbonyl,piperazinylmethyloxycarbonyl, groups of the formula of

and the like.

“Aromatic carbocyclylalkyloxyalkyl” means an alkyloxyalkyl substitutedwith one or more “aromatic carbocyclyl” described above. For example, itincludes benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl,benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, a groupof the formula of

and the like.

“Non-aromatic carbocyclylalkyloxyalkyl” means an alkyloxyalkylsubstituted with one or more “non-aromatic carbocyclyl” described above.“Non-aromatic carbocyclylalkyloxyalkyl” also includes “non-aromaticcarbocyclylalkyloxyalkyl” wherein the alkyl part bonded to thenon-aromatic carbocycle is substituted with the above “aromaticcarbocyclyl”. For example, it includes cyclopropylmethyloxymethyl,cyclobutylmethyloxymethyl, cyclopenthylmethyloxymethyl,cyclohexylmethyloxymethyl, a group of the formula of

and the like.

“Aromatic heterocyclylalkyloxyalkyl” means an alkyloxyalkyl substitutedwith one or more “aromatic heterocyclyl” described above. “Aromaticheterocyclylalkyloxyalkyl” also includes “aromaticheterocyclylalkyloxyalkyl” wherein the alkyl part bonded to the aromaticheterocycle is substituted with the above “aromatic carbocyclyl” and/or“non-aromatic carbocyclyl”. For example, it includespyridylmethyloxymethyl, furanylmethyloxymethyl,imidazolylmethyloxymethyl, indolylmethyloxymethyl,benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl,isoxazolylmethyloxymethyl, thiazolylmethyloxymethyl,isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl,isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl,benzoxazolylmethyloxymethyl, groups of the formula of

and the like.

“Non-aromatic heterocyclylalkyloxyalkyl” means an alkyloxyalkylsubstituted with one or more “non-aromatic heterocyclyl” describedabove. “Non-aromatic heterocyclylalkyloxyalkyl” also includes“non-aromatic heterocyclylalkyloxyalkyl” wherein the alkyl part bondedto the non-aromatic heterocycle is substituted with the above “aromaticcarbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”.For example, it includes tetrahydropyranylmethyloxymethyl,morpholinylmethyloxymethyl, morpholinylethyloxymethyl,piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups of theformula of

and the like.

The “aromatic carbocycle” part of “aromatic carbocyclyloxy”, “aromaticcarbocyclylcarbonyl”, “aromatic carbocyclyloxycarbonyl”, “aromaticcarbocyclylsulfanyl”, or “aromatic carbocyclylsulfonyl” is the same asthe above “aromatic carbocyclyl”.

“Aromatic carbocyclyloxy” means a group wherein “aromatic carbocycle” isbonded to oxygen atom. For example, it includes phenyloxy, naphthyloxyand the like.

“Aromatic carbocyclylcarbonyl” means a group wherein “aromaticcarbocycle” is bonded to carbonyl group. For example, it includesphenylcarbonyl, naphthylcarbonyl and the like.

“Aromatic carbocyclyloxycarbonyl” means a group wherein the above“aromatic carbocyclyloxy” is bonded to carbonyl group. For example, itincludes phenyloxycarbonyl, naphthyloxycarbonyl and the like.

“Aromatic carbocyclylsulfanyl” means a group wherein a hydrogen atombonded to a sulfur atom of sulfanyl group is replaced with “aromaticcarbocycle”. For example, it includes phenylsulfanyl, naphthylsulfanyland the like.

“Aromatic carbocyclylsulfonyl” means a group wherein “aromaticcarbocycle” is bonded to sulfonyl group. For example, it includesphenylsulfonyl, naphthylsulfonyl and the like.

The “non-aromatic carbocycle” part of “non-aromatic carbocyclyloxy”,“non-aromatic carbocyclylcarbonyl”, “non-aromaticcarbocyclyloxycarbonyl”, “non-aromatic carbocyclylsulfanyl”, or“non-aromatic carbocyclylsulfonyl” is the same as the above“non-aromatic carbocyclyl”.

“Non-aromatic carbocyclyloxy” means a group wherein “non-aromaticcarbocycle” is bonded to oxygen atom. For example, it includescyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like.

“Non-aromatic carbocyclylcarbonyl” means a group wherein “non-aromaticcarbocycle” is bonded to carbonyl group. For example, it includescyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and thelike.

“Non-aromatic carbocyclyloxycarbonyl” means a group wherein the above“non-aromatic carbocyclyloxy” is bonded to carbonyl group. For example,it includes cyclopropyloxycarbonyl, cyclohexyloxycarbonyl,cyclohexenyloxycarbonyl and the like.

“Non-aromatic carbocyclylsulfanyl” means a group wherein a hydrogen atombonded to a sulfur atom of sulfanyl group is replaced with “non-aromaticcarbocycle”. For example, it includes cyclopropylsulfanyl,cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.

“Non-aromatic carbocyclylsulfonyl” means a group wherein “non-aromaticcarbocycle” is bonded to sulfonyl group. For example, it includescyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and thelike.

The “aromatic heterocycle” part of “aromatic heterocyclyloxy”, “aromaticheterocyclylcarbonyl”, “aromatic heterocyclyloxycarbonyl”, “aromaticheterocyclylsulfanyl”, or “aromatic heterocyclylsulfonyl” is the same asthe above “aromatic heterocyclyl”.

“Aromatic heterocyclyloxy” means a group wherein “aromatic heterocycle”is bonded to oxygen atom. For example, it includes pyridyloxy,oxazolyloxy and the like.

“Aromatic heterocyclylcarbonyl” means a group wherein “aromaticheterocycle” is bonded to carbonyl group. For example, it includespyridylcarbonyl, oxazolylcarbonyl and the like.

“Aromatic heterocyclyloxycarbonyl” means a group wherein the above“aromatic heterocyclyloxy” is bonded to carbonyl group. For example, itincludes pyridyloxycarbonyl, oxazolyloxycarbonyl and the like.

“Aromatic heterocyclylsulfanyl” means a group wherein a hydrogen atombonded to a sulfur atom of sulfanyl group is replaced with “aromaticheterocycle”. For example, it includes pyridylsulfanyl, oxazolylsulfanyland the like.

“Aromatic heterocyclylsulfonyl” means a group wherein “aromaticheterocycle” is bonded to sulfonyl group. For example, it includespyridylsulfonyl, oxazolylsulfonyl and the like.

The “non-aromatic heterocycle” part of “non-aromatic heterocyclyloxy”,“non-aromatic heterocyclylcarbonyl”, “non-aromaticheterocyclyloxycarbonyl”, “non-aromatic heterocyclylsulfanyl”, or“non-aromatic heterocyclylsulfonyl” is the same as the above“non-aromatic heterocyclyl”.

“Non-aromatic heterocyclyloxy” means a group wherein “non-aromaticheterocycle” is bonded to oxygen atom. For example, it includespiperidinyloxy, tetrahydrofuryloxy and the like.

“Non-aromatic heterocyclylcarbonyl” means a group wherein “non-aromaticheterocycle” is bonded to carbonyl group. For example, it includespiperidinylcarbonyl, tetrahydrofurylcarbonyl and the like.

“Non-aromatic heterocyclyloxycarbonyl” means a group wherein the above“non-aromatic heterocyclyloxy” is bonded to carbonyl group. For example,it includes piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and thelike.

“Non-aromatic heterocyclylsulfanyl” means a group wherein a hydrogenatom bonded to a sulfur atom of sulfanyl group is replaced with“non-aromatic heterocycle”. For example, it includespiperidinylsulfanyl, tetrahydrofurylsulfanyl and the like.

“Non-aromatic heterocyclylsulfonyl” means a group wherein “non-aromaticheterocycle” is bonded to sulfonyl group. For example, it includespiperidinylsulfonyl, tetrahydrofurylsulfonyl and the like.

The substituents of “substituted or unsubstituted alkyl”, “substitutedor unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”,“substituted or unsubstituted alkyloxy”, “substituted or unsubstitutedalkenyloxy”, “substituted or unsubstituted alkynyloxy”, “substituted orunsubstituted alkylcarbonyl”, “substituted or unsubstitutedalkenylcarbonyl”, “substituted or unsubstituted alkynylcarbonyl”,“substituted or unsubstituted alkylsulfonyl”, “substituted orunsubstituted alkenylsulfonyl”, “substituted or unsubstitutedalkynylsulfonyl”, “substituted or unsubstituted alkylcarbonyloxy”,“substituted or unsubstituted alkenylcarbonyloxy”, “substituted orunsubstituted alkynylcarbonyloxy”, “substituted or unsubstitutedalkyloxycarbonyl”, “substituted or unsubstituted alkenyloxycarbonyl”,“substituted or unsubstituted alkynyloxycarbonyl”, “substituted orunsubstituted alkylsulfanyl”, “substituted or unsubstitutedalkenylsulfanyl”, “substituted or unsubstituted alkynylsulfanyl”,“substituted or unsubstituted alkylsulfinyl”, “substituted orunsubstituted alkenylsulfinyl”, and “substituted or unsubstitutedalkynylsulfinyl” include the following substituents. A carbon atom atany positions may be bonded to one or more group(s) selected from thefollowing substituents.

Substituents: halogen, hydroxy, carboxy, amino, imino, formyl, sulfanyl,sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl,cyano, nitro, azido, hydrazino optionally substituted with thesubstituent group A, ureido optionally substituted with the substituentgroup A, amidino optionally substituted with the substituent group A,guanidino optionally substituted with the substituent group A, aminooptionally substituted with the substituent group B, imino optionallysubstituted with the substituent group D, alkyloxy, alkenyloxy,alkynyloxy, haloalkyloxy, haloalkenyloxy, haloalkynyloxy, alkylcarbonyloptionally substituted with the substituent group E, alkenylcarbonyloptionally substituted with the substituent group E, alkynylcarbonyloptionally substituted with the substituent group E, alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl, haloalkylsulfonyl,haloalkenylsulfonyl, haloalkynylsulfonyl, alkylcarbonyloxy,alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl,alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl,alkynylsulfanyl, haloalkylsulfanyl, haloalkenylsulfanyl,haloalkynylsulfanyl, carbamoyl optionally substituted with thesubstituent group F, sulfamoyl optionally substituted with thesubstituent group F, aromatic carbocyclyl optionally substituted withthe substituent group C, non-aromatic carbocyclyl optionally substitutedwith the substituent group C, aromatic heterocyclyl optionallysubstituted with the substituent group C, non-aromatic heterocyclyloptionally substituted with the substituent group C, aromaticcarbocyclyloxy optionally substituted with the substituent group C,non-aromatic carbocyclyloxy optionally substituted with the substituentgroup C, aromatic heterocyclyloxy optionally substituted with thesubstituent group C, non-aromatic heterocyclyloxy optionally substitutedwith the substituent group C, aromatic carbocyclylcarbonyl optionallysubstituted with the substituent group C, non-aromaticcarbocyclylcarbonyl optionally substituted with the substituent group C,aromatic heterocyclylcarbonyl optionally substituted with thesubstituent group C, non-aromatic heterocyclylcarbonyl optionallysubstituted with the substituent group C, aromaticcarbocyclyloxycarbonyl optionally substituted with the substituent groupC, non-aromatic carbocyclyloxycarbonyl optionally substituted with thesubstituent group C, aromatic heterocyclyloxycarbonyl optionallysubstituted with the substituent group C, non-aromaticheterocyclyloxycarbonyl optionally substituted with the substituentgroup C, aromatic carbocyclylalkyloxy optionally substituted with thesubstituent group C, non-aromatic carbocyclylalkyloxy optionallysubstituted with the substituent group C, aromatic heterocyclylalkyloxyoptionally substituted with the substituent group C, non-aromaticheterocyclylalkyloxy optionally substituted with the substituent groupC, aromatic carbocyclylalkyloxycarbonyl optionally substituted with thesubstituent group C, non-aromatic carbocyclylalkyloxycarbonyl optionallysubstituted with the substituent group C, aromaticheterocyclylalkyloxycarbonyl optionally substituted with the substituentgroup C, non-aromatic heterocyclylalkyloxycarbonyl optionallysubstituted with the substituent group C, aromatic carbocyclylsulfanyloptionally substituted with the substituent group C, non-aromaticcarbocyclylsulfanyl optionally substituted with the substituent group C,aromatic heterocyclylsulfanyl optionally substituted with thesubstituent group C, non-aromatic heterocyclylsulfanyl optionallysubstituted with the substituent group C, aromatic carbocyclylsulfonyloptionally substituted with the substituent group C, non-aromaticcarbocyclylsulfonyl optionally substituted with the substituent group C,aromatic heterocyclylsulfonyl optionally substituted with thesubstituent group C, and non-aromatic heterocyclylsulfonyl optionallysubstituted with the substituent group C.

The substituent group A are alkyl, and haloalkyl.

The substituent group B are hydroxy, cyano, alkyl, haloalkyl,alkylcarbonyl, haloalkylcarbonyl, alkylsulfonyl, haloalkylsulfonyl,carbamoyl optionally substituted with the substituent group A, aromaticcarbocyclyl optionally substituted with the substituent group C,non-aromatic carbocyclyl optionally substituted with the substituentgroup C, aromatic heterocyclyl optionally substituted with thesubstituent group C, non-aromatic heterocyclyl optionally substitutedwith the substituent group C, aromatic carbocyclylalkyl optionallysubstituted with the substituent group C, non-aromatic carbocyclylalkyloptionally substituted with the substituent group C, aromaticheterocyclylalkyl optionally substituted with the substituent group C,non-aromatic heterocyclylalkyl optionally substituted with thesubstituent group C, aromatic carbocyclylcarbonyl optionally substitutedwith the substituent group C, non-aromatic carbocyclylcarbonyloptionally substituted with the substituent group C, aromaticheterocyclylcarbonyl optionally substituted with the substituent groupC, non-aromatic heterocyclylcarbonyl optionally substituted with thesubstituent group C, aromatic carbocyclylaminocarbonyl optionallysubstituted with the substituent group C, non-aromaticcarbocyclylaminocarbonyl optionally substituted with the substituentgroup C, aromatic heterocyclylaminocarbonyl optionally substituted withthe substituent group C, and non-aromatic heterocyclylaminocarbonyloptionally substituted with the substituent group C.

The substituent group C are halogen, hydroxy, cyano, alkyl, haloalkyl,alkyloxy, haloalkyloxy, alkylcarbonyl, haloalkylcarbonyl, aminooptionally substituted with alkyl or haloalkyl, alkylsulfonyl,haloalkylsulfonyl, alkylsulfanyl, and haloalkylsulfanyl.

The substituent group D are hydroxy, alkyl, alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, alkyloxy, alkenyloxy, alkynyloxy,haloalkyloxy, haloalkenyloxy, haloalkynyloxy, alkylcarbonyl,alkenylcarbonyl, alkynylcarbonyl, haloalkylcarbonyl,haloalkenylcarbonyl, haloalkynylcarbonyl, amino, alkylamino,haloalkylamino, aromatic carbocyclyl optionally substituted with thesubstituent group C, non-aromatic carbocyclyl optionally substitutedwith the substituent group C, aromatic heterocyclyl optionallysubstituted with the substituent group C, and non-aromatic heterocyclyloptionally substituted with the substituent group C.

The substituent group E are halogen, hydroxy, cyano, alkyloxy,haloalkyloxy, amino optionally substituted with the substituent group B,aromatic carbocyclyl optionally substituted with the substituent groupC, non-aromatic carbocyclyl optionally substituted with the substituentgroup C, aromatic heterocyclyl optionally substituted with thesubstituent group C, non-aromatic heterocyclyl optionally substitutedwith the substituent group C, aromatic carbocyclyloxy optionallysubstituted with the substituent group C, non-aromatic carbocyclyloxyoptionally substituted with the substituent group C, aromaticheterocyclyloxy optionally substituted with the substituent group C,non-aromatic heterocyclyloxy optionally substituted with the substituentgroup C, aromatic carbocyclylsulfonyl optionally substituted with thesubstituent group C, non-aromatic carbocyclylsulfonyl optionallysubstituted with the substituent group C, aromatic heterocyclylsulfonyloptionally substituted with the substituent group C, non-aromaticheterocyclylsulfonyl optionally substituted with the substituent groupC, aromatic carbocyclylsulfanyl optionally substituted with thesubstituent group C, non-aromatic carbocyclylsulfanyl optionallysubstituted with the substituent group C, aromatic heterocyclylsulfanyloptionally substituted with the substituent group C, and non-aromaticheterocyclylsulfanyl optionally substituted with the substituent groupC.

The substituent group F are hydroxy, cyano, amino, alkylamino, alkyl,haloalkyl, hydroxyalkyl, alkylcarbonyl, alkylsulfonyl, aromaticcarbocyclyl optionally substituted with the substituent group C,non-aromatic carbocyclyl optionally substituted with the substituentgroup C, aromatic heterocyclyl optionally substituted with thesubstituent group C, non-aromatic heterocyclyl optionally substitutedwith the substituent group C, aromatic carbocyclylalkyl optionallysubstituted with the substituent group C, non-aromatic carbocyclylalkyloptionally substituted with the substituent group C, aromaticheterocyclylalkyl optionally substituted with the substituent group C,and non-aromatic heterocyclylalkyl optionally substituted with thesubstituent group C.

“Optionally substituted with the substituent group A” include that it isoptionally substituted with one or more, same or different substituentsselected from the substituent group A. An embodiment includes that it isoptionally substituted with same or different substituents selected fromthe substituent group A at one to six position(s). Another embodimentincludes that it is optionally substituted with same or differentsubstituents selected from the substituent group A at one to threeposition(s).

“Optionally substituted with the substituent group B”, “optionallysubstituted with the substituent group C”, “optionally substituted withthe substituent group D”, “optionally substituted with the substituentgroup E”, and “optionally substituted with the substituent group F” arethe same as the above-mentioned.

The substituents on the ring of “aromatic carbocycle”, “non-aromaticcarbocycle”, “aromatic heterocycle” or “non-aromatic heterocycle” of“substituted or unsubstituted aromatic carbocyclyl”, “substituted orunsubstituted non-aromatic carbocyclyl”, “substituted or unsubstitutedaromatic heterocyclyl”, and “substituted or unsubstituted non-aromaticheterocyclyl”, “substituted or unsubstituted aromatic carbocyclyloxy”,“substituted or unsubstituted non-aromatic carbocyclyloxy”, “substitutedor unsubstituted aromatic heterocyclyloxy”, and “substituted orunsubstituted non-aromatic heterocyclyloxy”, “substituted orunsubstituted aromatic carbocyclylcarbonyl”, “substituted orunsubstituted non-aromatic carbocyclylcarbonyl”, “substituted orunsubstituted aromatic heterocyclylcarbonyl”, and “substituted orunsubstituted non-aromatic heterocyclylcarbonyl”, “substituted orunsubstituted aromatic carbocyclyloxycarbonyl”, “substituted orunsubstituted non-aromatic carbocyclyloxycarbonyl”, “substituted orunsubstituted aromatic heterocyclyloxycarbonyl”, and “substituted orunsubstituted non-aromatic heterocyclyloxycarbonyl”, “substituted orunsubstituted aromatic carbocyclylsulfanyl”, “substituted orunsubstituted non-aromatic carbocyclylsulfanyl”, “substituted orunsubstituted aromatic heterocyclylsulfanyl”, and “substituted orunsubstituted non-aromatic heterocyclylsulfanyl”, “substituted orunsubstituted aromatic carbocyclylsulfonyl”, “substituted orunsubstituted non-aromatic carbocyclylsulfonyl”, “substituted orunsubstituted aromatic heterocyclylsulfonyl”, and “substituted orunsubstituted non-aromatic heterocyclylsulfonyl” include the followingsubstituents. An atom at any positions on the ring may be bonded to oneor more group(s) selected from the following substituents.

Substituents: halogen, hydroxy, carboxy, amino, imino, formyl, sulfanyl,sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl,cyano, nitro, azido, hydrazino optionally substituted with thesubstituent group A, ureido optionally substituted with the substituentgroup A, amidino optionally substituted with the substituent group A,guanidino optionally substituted with the substituent group A, aminooptionally substituted with the substituent group B, imino optionallysubstituted with the substituent group D, alkyl, alkenyl, alkynyl,haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy,haloalkenyloxy, haloalkynyloxy, alkyloxyalkyl, haloalkyloxyalkyl,alkyloxyalkyloxy, alkylcarbonyl optionally substituted with thesubstituent group E, alkenylcarbonyl optionally substituted with thesubstituent group E, alkynylcarbonyl optionally substituted with thesubstituent group E, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl,haloalkylsulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl,alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl,alkenylsulfanyl, alkynylsulfanyl, haloalkylsulfanyl,haloalkenylsulfanyl, haloalkynylsulfanyl, carbamoyl optionallysubstituted with the substituent group F, famoyl optionally substitutedwith the substituent group F, aromatic carbocyclyl optionallysubstituted with the substituent group C, non-aromatic carbocyclyloptionally substituted with the substituent group C, aromaticheterocyclyl optionally substituted with the substituent group C,non-aromatic heterocyclyl optionally substituted with the substituentgroup C, aromatic carbocyclyloxy optionally substituted with thesubstituent group C, non-aromatic carbocyclyloxy optionally substitutedwith the substituent group C, aromatic heterocyclyloxy optionallysubstituted with the substituent group C, non-aromatic heterocyclyloxyoptionally substituted with the substituent group C, aromaticcarbocyclylcarbonyl optionally substituted with the substituent group C,non-aromatic carbocyclylcarbonyl optionally substituted with thesubstituent group C, aromatic heterocyclylcarbonyl optionallysubstituted with the substituent group C, non-aromaticheterocyclylcarbonyl optionally substituted with the substituent groupC, aromatic carbocyclyloxycarbonyl optionally substituted with thesubstituent group C, non-aromatic carbocyclyloxycarbonyl optionallysubstituted with the substituent group C, aromaticheterocyclyloxycarbonyl optionally substituted with the substituentgroup C, non-aromatic heterocyclyloxycarbonyl optionally substitutedwith the substituent group C, aromatic carbocyclylalkyl optionallysubstituted with the substituent group C, non-aromatic carbocyclylalkyloptionally substituted with the substituent group C, aromaticheterocyclylalkyl optionally substituted with the substituent group C,non-aromatic heterocyclylalkyl optionally substituted with thesubstituent group C, aromatic carbocyclylalkyloxy optionally substitutedwith the substituent group C, non-aromatic carbocyclylalkyloxyoptionally substituted with the substituent group C, aromaticheterocyclylalkyloxy optionally substituted with the substituent groupC, non-aromatic heterocyclylalkyloxy optionally substituted with thesubstituent group C, aromatic carbocyclylalkyloxycarbonyl optionallysubstituted with the substituent group C, non-aromaticcarbocyclylalkyloxycarbonyl optionally substituted with the substituentgroup C, aromatic heterocyclylalkyloxycarbonyl optionally substitutedwith the substituent group C, non-aromatic heterocyclylalkyloxycarbonyloptionally substituted with the substituent group C, aromaticcarbocyclylalkyloxyalkyl optionally substituted with the substituentgroup C, non-aromatic carbocyclylalkyloxyalkyl optionally substitutedwith the substituent group C, aromatic heterocyclylalkyloxyalkyloptionally substituted with the substituent group C, non-aromaticheterocyclylalkyloxyalkyl optionally substituted with the substituentgroup C, aromatic carbocyclylsulfanyl optionally substituted with thesubstituent group C, non-aromatic carbocyclylsulfanyl optionallysubstituted with the substituent group C, aromatic heterocyclylsulfanyloptionally substituted with the substituent group C, non-aromaticheterocyclylsulfanyl optionally substituted with the substituent groupC, non-aromatic carbocyclylsulfonyl optionally substituted with thesubstituent group C, aromatic carbocyclylsulfonyl optionally substitutedwith the substituent group C, aromatic heterocyclylsulfonyl optionallysubstituted with the substituent group C, and non-aromaticheterocyclylsulfonyl optionally substituted with the substituent groupC.

Additionally, “substituted or unsubstituted non-aromatic carbocyclyl”and “substituted or unsubstituted non-aromatic heterocyclyl” may besubstituted with “oxo”. In this case, it means a group wherein twohydrogen atoms on the same carbon atom are substituted as below.

The non-aromatic carbocycle or non-aromatic heterocycle part of theabove “substituted or unsubstituted non-aromatic carbocyclyloxy”,“substituted or unsubstituted non-aromatic heterocyclyloxy”,“substituted or unsubstituted non-aromatic carbocyclylcarbonyl”,“substituted or unsubstituted non-aromatic heterocyclylcarbonyl”,“substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl”,“substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl”,“substituted or unsubstituted non-aromatic carbocyclylsulfanyl”,“substituted or unsubstituted non-aromatic heterocyclylsulfanyl”,“substituted or unsubstituted non-aromatic carbocyclylsulfonyl”, and“substituted or unsubstituted non-aromatic heterocyclylsulfonyl” may besubstituted with “oxo” as above.

“Substituted or unsubstituted amino” includes amino optionallysubstituted with the above substituent group B at one or twoposition(s).

An embodiment of “substituted or unsubstituted amino” is amino,methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino,cyclopropylamino, cyclohexylamino, benzylamino, acetylamino,benzoylamino, methylsulfonylamino, tetrahydropyranylamino,tetrahydrofuranylamino, morpholino amino, morpholinylamino,piperidinylamino, piperazinylamino and the like. Another embodiment of“substituted or unsubstituted amino” is amino, methylamino,dimethylamino, ethylmethylamino, diethylamino, acetylamino,methylsulfonylamino, tetrahydropyranylamino, tetrahydrofuranylamino,morpholinoamino, piperidinylamino and the like.

An embodiment of “substituted or unsubstituted amidino” and “substitutedor unsubstituted guanidino” include amidino and guanidine optionallysubstituted with the above substituent group B at one or twoposition(s).

“Substituted or unsubstituted imino” includes imino optionallysubstituted with the above substituent group D.

An embodiment of “substituted or unsubstituted imino” is imino,methylimino, ethylimino, cyclopropylimino, cyclohexylimino, acetylimino,tetrahydropyranylimino, tetrahydrofuranylimino, morpholinoimino,morpholinylimino, piperidinylimino, piperazinylimino and the like.

“Substituted or unsubstituted carbamoyl” includes aminocarbonyloptionally substituted with the above substituent group F at one or twoposition(s).

An embodiment of “substituted or unsubstituted carbamoyl” is carbamoyl,N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-n-propylaminocarbamoyl, N-isopropylcarbamoyl,N-morpholinocarbamoyl, N-tetrahydrofuranylcarbamoyl,N-piperidylcarbamoyl, N-tetrahydropyranylcarbamoyl, N-benzylcarbamoyl,N-acetylcarbamoyl, N-methylsulfonylcarbamoyl,N-(2,2,2-trifluoroethyl)carbamoyl, N-(2-hydroxy-1-methylethyl)carbamoyland the like. Another embodiment of “substituted or unsubstitutedcarbamoyl” is carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl,N-n-propylamino carbamoyl, N-isopropylcarbamoyl, N-morpholinocarbamoyl,N-tetrahydrofuranylcarbamoyl, N-piperidylcarbamoyl,N-tetrahydropyranylcarbamoyl, N-methylsulfonylcarbamoyl,N-(2,2,2-trifluoroethyl)carbamoyl, N-(2-hydroxy-1-methylethyl)carbamoyland the like.

“Substituted or unsubstituted sulfamoyl” includes aminosulfonyloptionally substituted with the above substituent group F.

An embodiment of “substituted or unsubstituted sulfamoyl” is sulfamoyl,N-methylsulfamoyl, N,N-dimethylsulfamoyl, N-ethyl-N-methylsulfamoyl,N,N-diethylsulfamoyl, N-n-propylaminosulfamoyl, N-isopropylsulfamoyl,N-morpholinosulfamoyl, N-tetrahydrofuranylsulfamoyl,N-piperidylsulfamoyl, N-tetrahydropyranylsulfamoyl, N-benzylsulfamoyl,N-acetylsulfamoyl, N-methylsulfonylsulfamoyl and the like. Anotherembodiment of “substituted or unsubstituted sulfamoyl” is sulfamoyl,N-methylsulfamoyl, N,N-dimethylsulfamoyl, N-n-propylaminosulfamoyl,N-isopropylsulfamoyl, N-morpholinosulfamoyl,N-tetrahydrofuranylsulfamoyl, N-piperidylsulfamoyl,N-tetrahydropyranylsulfamoyl, N-methylsulfonylsulfamoyl and the like.

An embodiment of a compound represented by formula (I) or apharmaceutically acceptable salt thereof includes the compound indicatedby all possible combination of the following each substituent.

(1) In the compound according to the above 1)

wherein the formula:

is the group represented by the following formula

wherein each substituent is the same as the above 1),

the compound wherein (i) is (i1) (hereinafter referred to as I-1),

the compound wherein (i) is (i2) (hereinafter referred to as I-2),

the compound wherein (i) is (i3) (hereinafter referred to as I-3),

the compound wherein (i) is (i4) (hereinafter referred to as I-4),

the compound wherein (i) is (i1) or (i2) (hereinafter referred to asI-5), the compound wherein (i) is (i1) or (i4) (hereinafter referred toas I-6),

(2) the compound wherein R¹ is a hydrogen atom (hereinafter referred toas r1-1),

(3) the compound wherein R² is substituted or unsubstituted amino,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, or

a group represented by the following formula: —(CR^(2a)R^(2b))_(n)—R²wherein R^(2a) is each independently a hydrogen atom, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkyloxy,R^(2b) is each independently a hydrogen atom, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkyloxy, orR^(2a) and R^(2b) which are attached to the same carbon atom may betaken together to form oxo, substituted or unsubstituted non-aromaticcarbocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl;R^(2c) is substituted or unsubstituted aromatic carbocyclyl, substitutedor unsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy,substituted or unsubstituted non-aromatic carbocyclyloxy, substituted orunsubstituted aromatic heterocyclyloxy, substituted or unsubstitutednon-aromatic heterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylamino, substituted or unsubstituted non-aromaticcarbocyclylamino, substituted or unsubstituted aromaticheterocyclylamino, substituted or unsubstituted non-aromaticheterocyclylamino, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;n is an integer from 1 to 3 (hereinafter referred to as r2-1),

the compound wherein R² is a group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)

wherein R^(2a) is each independently a hydrogen atom, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkyloxy,R^(2b) is each independently a hydrogen atom, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkyloxy, orR^(2a) and R^(2b) which are attached to the same carbon atom may betaken together to form oxo, substituted or unsubstituted non-aromaticcarbocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl;R^(2c) is substituted or unsubstituted aromatic carbocyclyl, substitutedor unsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy,substituted or unsubstituted non-aromatic carbocyclyloxy, substituted orunsubstituted aromatic heterocyclyloxy, substituted or unsubstitutednon-aromatic heterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylamino, substituted or unsubstituted non-aromaticcarbocyclylamino, substituted or unsubstituted aromaticheterocyclylamino, substituted or unsubstituted non-aromaticheterocyclylamino, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;n is an integer from 1 to 3 (hereinafter referred to as r2-2),

the compound wherein R² is substituted or unsubstituted amino,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, or substituted or unsubstituted non-aromaticheterocyclyl (hereinafter referred to as r2-3),

the compound wherein R² is aromatic carbocyclyl optionally substitutedwith the substituent group G (the substituent group C, aromaticcarbocyclyl optionally substituted with the substituent group C,non-aromatic carbocyclyl optionally substituted with the substituentgroup C, aromatic heterocyclyl optionally substituted with thesubstituent group C, non-aromatic heterocyclyl optionally substitutedwith the substituent group C, aromatic carbocyclylalkyl optionallysubstituted with the substituent group C, non-aromatic carbocyclylalkyloptionally substituted with the substituent group C, aromaticheterocyclylalkyl optionally substituted with the substituent group C,non-aromatic heterocyclylalkyl optionally substituted with thesubstituent group C, aromatic carbocyclylalkyloxy optionally substitutedwith the substituent group C, non-aromatic carbocyclylalkyloxyoptionally substituted with the substituent group C, aromaticheterocyclylalkyloxy optionally substituted with the substituent groupC, non-aromatic heterocyclylalkyloxy optionally substituted with thesubstituent group C, aromatic carbocyclylamino optionally substitutedwith the substituent group C, non-aromatic carbocyclylamino optionallysubstituted with the substituent group C, aromatic heterocyclylaminooptionally substituted with the substituent group C, and non-aromaticheterocyclylamino optionally substituted with the substituent group C),non-aromatic carbocyclyl optionally substituted with the substituentgroup H (the substituent group G, and oxo), aromatic heterocyclyloptionally substituted with the substituent group G, non-aromaticheterocyclyl optionally substituted with the substituent group H,aromatic carbocyclylamino optionally substituted with the substituentgroup G, non-aromatic carbocyclylamino optionally substituted with thesubstituent group H, aromatic heterocyclylamino optionally substitutedwith the substituent group G, non-aromatic heterocyclylamino optionallysubstituted with the substituent group H, amino optionally substitutedwith the substituent group I (hydroxy, cyano, alkyl, haloalkyl,alkylsulfonyl, haloalkylsulfonyl), or

a group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein R^(2a) is each independently a hydrogen atom, halogen, alkyloptionally substituted with the substituent group J (halogen, hydroxy,non-aromatic carbocyclyl optionally substituted with halogen), alkyloxyoptionally substituted with the substituent group J,R^(2b) is each independently a hydrogen atom, halogen, alkyl optionallysubstituted with the substituent group J, alkyloxy optionallysubstituted with the substituent group J, orR^(2a) and R^(2b) which are attached to the same carbon atom at any oneposition may be taken together to form oxo, or non-aromatic carbocyclyloptionally substituted with halogen; R^(2c) is aromatic carbocyclyloptionally substituted with the substituent group G, non-aromaticcarbocyclyl optionally substituted with the substituent group H,aromatic heterocyclyl optionally substituted with the substituent groupG, non-aromatic heterocyclyl optionally substituted with the substituentgroup H, aromatic carbocyclyloxy optionally substituted with thesubstituent group G, non-aromatic carbocyclyloxy optionally substitutedwith the substituent group H, aromatic heterocyclyloxy optionallysubstituted with the substituent group G, non-aromatic heterocyclyloxyoptionally substituted with the substituent group H, aromaticcarbocyclylamino optionally substituted with the substituent group G,non-aromatic carbocyclylamino optionally substituted with thesubstituent group H, aromatic heterocyclylamino optionally substitutedwith the substituent group G, non-aromatic heterocyclylamino optionallysubstituted with the substituent group H, aromatic carbocyclylsulfonyloptionally substituted with the substituent group G, non-aromaticcarbocyclylsulfonyl optionally substituted with the substituent group H,aromatic heterocyclylsulfonyl optionally substituted with thesubstituent group G, or non-aromatic heterocyclylsulfonyl optionallysubstituted with the substituent group H;n is an integer from 1 to 3 (hereinafter referred to as r2-4),

the compound wherein R² is aromatic carbocyclyl optionally substitutedwith the substituent group G, non-aromatic carbocyclyl optionallysubstituted with the substituent group H, aromatic heterocyclyloptionally substituted with the substituent group G, non-aromaticheterocyclyl optionally substituted with the substituent group H, or

a group represented by the following formula: —C(R^(2a)R^(2b))—R^(2c)wherein R^(2a) and R^(2b) are each independently a hydrogen atom,halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, orR^(2a) and R^(2b) which are attached to the same carbon atom at any oneposition may be taken together to form non-aromatic carbocyclyloptionally substituted with halogen;R^(2c) is aromatic carbocyclyl optionally substituted with thesubstituent group G, non-aromatic carbocyclyl optionally substitutedwith the substituent group H, aromatic heterocyclyl optionallysubstituted with the substituent group G, non-aromatic heterocyclyloptionally substituted with the substituent group H (hereinafterreferred to as r2-5),

(4) the compound wherein R⁴ is a hydrogen atom, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted carbamoyl, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, orsubstituted or unsubstituted aromatic heterocyclyl (hereinafter referredto as r4-1),

the compound wherein R⁴ is a hydrogen atom, alkyl, haloalkyl,hydroxyalkyl, alkenyl optionally substituted with aromatic carbocyclyl,carbamoyl optionally substituted with the substituent group F, aromaticcarbocyclyl optionally substituted with the substituent group C,non-aromatic carbocyclyl optionally substituted with the substituentgroup C, aromatic heterocyclyl optionally substituted with thesubstituent group C, or non-aromatic heterocyclyl optionally substitutedwith the substituent group C (hereinafter referred to as r4-2),

the compound wherein R⁴ is a hydrogen atom, alkyl, haloalkyl, oraromatic heterocyclyl optionally substituted with the substituent groupC (hereinafter referred to as r4-3),

(5) the compound wherein R⁵ is a hydrogen atom, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkylcarbonyl, substituted or unsubstitutedalkyloxycarbonyl, or substituted or unsubstituted carbamoyl (hereinafterreferred to as r5-1),

the compound wherein R⁵ is a hydrogen atom, halogen, alkyl optionallysubstituted with the substituent group K (halogen, hydroxy, cyano,alkyl, haloalkyl, hydroxyalkyl, alkylsulfonyl, haloalkylsulfonyl, aminooptionally substituted with the substituent group C, carbamoyloptionally substituted with the substituent group F, non-aromaticheterocyclyl optionally substituted with the substituent group C),ycarbamoyl optionally substituted with the substituent group L (alkyl,haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl), alkenyl,haloalkenyl, alkylcarbonyl, haloalkylcarbonyl, alkyloxycarbonyl(hereinafter referred to as r5-2),

the compound wherein R⁵ is a hydrogen atom, alkyl, haloalkyl,hydroxyalkyl, alkenyl, alkylcarbonyl, haloalkylcarbonyl, alkylcarbamoyl,hydroxyalkylcarbamoyl, alkylaminoalkylcarbamoyl or alkylaminoalkyl(hereinafter referred to as r5-3),

(6) the compound wherein R⁶ is a hydrogen atom, halogen, amidino,guanidino, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkylcarbonyl, orsubstituted or unsubstituted carbamoyl (hereinafter referred to asr6-1),

the compound wherein R⁶ is a hydrogen atom, halogen, guanidino, alkyl,haloalkyl, hydroxyalkyl, alkenyl, alkylcarbonyl, carbamoyl optionallysubstituted with the substituent group M (hydroxy, cyano, alkyl,haloalkyl, hydroxyalkyl, alkylaminoalkyl, alkyloxy, haloalkyloxy,alkylsulfonyl, haloalkylsulfonyl) (hereinafter referred to as r6-2),

the compound wherein R⁶ is a hydrogen atom, halogen, alkyl, haloalkyl,hydroxyalkyl, alkenyl, carbamoyl, or alkylcarbamoyl (hereinafterreferred to as r6-3).

An embodiment of a pharmaceutical composition for inhibiting a TRPV4receptor containing a compound represented by formula (II) or apharmaceutically acceptable salt thereof includes the pharmaceuticalcomposition for inhibiting a TRPV4 receptor containing the compoundindicated by all possible combination of the following each substituent.

(7) In the compound according to the above 11)

wherein the formula:

is the group represented by the following formula

wherein R⁴, R⁵, R⁶, and R⁷ are the same as the above 11); —X1- is—N(R³)— or —S—,

the compound wherein (ii) is (ii1) (hereinafter referred to as II-1),

the compound wherein (ii) is (ii2) (hereinafter referred to as II-2),

the compound wherein (ii) is (ii3) (hereinafter referred to as II-3),

the compound wherein (ii) is (ii4) (hereinafter referred to as II-4),

the compound wherein (ii) is (ii1) or (ii2) (hereinafter referred to asII-5),

the compound wherein (ii) is (ii1) or (ii4) (hereinafter referred to asII-6),

(8) the compound wherein -L- is —N(R¹)—, —N(R¹)—C(═O)—, —N(R¹)—SO₂—,—C(═O)—N(R¹)—, or —(CR^(1a)R^(1b))₂—O—,

R¹ is a hydrogen atom;R^(1a) is each independently a hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy;R^(1b) is each independently a hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy (hereinafter referred to as L-1),

the compound wherein -L- is —N(R¹)—, or —N(R¹)—C(═O)—,

R¹ is a hydrogen atom (hereinafter referred to as L-2),

the compound wherein -L- is —N(R¹)—, —N(R¹)—C(═O)—, or —C(═O)—N(R¹)—,

R¹ is a hydrogen atom (hereinafter referred to as L-3),

the compound wherein -L- is —N(R¹)—,

R¹ is a hydrogen atom (hereinafter referred to as L-4),

(9) the compound wherein R² is substituted or unsubstituted amino,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, or

a group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein R^(2a) is each independently a hydrogen atom, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkyloxy,R^(2b) is each independently a hydrogen atom, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkyloxy, orR^(2a) and R^(2b) which are attached to the same carbon atom may betaken together to form oxo, substituted or unsubstituted non-aromaticcarbocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl;R^(2c) is substituted or unsubstituted aromatic carbocyclyl, substitutedor unsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy,substituted or unsubstituted non-aromatic carbocyclyloxy, substituted orunsubstituted aromatic heterocyclyloxy, substituted or unsubstitutednon-aromatic heterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylamino, substituted or unsubstituted non-aromaticcarbocyclylamino, substituted or unsubstituted aromaticheterocyclylamino, substituted or unsubstituted non-aromaticheterocyclylamino, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;n is an integer from 1 to 3 (hereinafter referred to as r2′-1),

the compound wherein R² is a group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)

wherein R^(2a) is each independently a hydrogen atom, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkyloxy,R^(2b) is each independently a hydrogen atom, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkyloxy, orR^(2a) and R^(2b) which are attached to the same carbon atom may betaken together to form oxo, substituted or unsubstituted non-aromaticcarbocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl;R^(2c) is substituted or unsubstituted aromatic carbocyclyl, substitutedor unsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy,substituted or unsubstituted non-aromatic carbocyclyloxy, substituted orunsubstituted aromatic heterocyclyloxy, substituted or unsubstitutednon-aromatic heterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylamino, substituted or unsubstituted non-aromaticcarbocyclylamino, substituted or unsubstituted aromaticheterocyclylamino, substituted or unsubstituted non-aromaticheterocyclylamino, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl;n is an integer from 1 to 3 (hereinafter referred to as r2′-2),

the compound wherein R² is substituted or unsubstituted amino,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, or substituted or unsubstituted non-aromaticheterocyclyl (hereinafter referred to as r2′-3),

the compound wherein R² is aromatic carbocyclyl optionally substitutedwith the substituent group G (the substituent group C, aromaticcarbocyclyl optionally substituted with the substituent group C,non-aromatic carbocyclyl optionally substituted with the substituentgroup C, aromatic heterocyclyl optionally substituted with thesubstituent group C, non-aromatic heterocyclyl optionally substitutedwith the substituent group C, aromatic carbocyclylalkyl optionallysubstituted with the substituent group C, non-aromatic carbocyclylalkyloptionally substituted with the substituent group C, aromaticheterocyclylalkyl optionally substituted with the substituent group C,non-aromatic heterocyclylalkyl optionally substituted with thesubstituent group C, aromatic carbocyclylalkyloxy optionally substitutedwith the substituent group C, non-aromatic carbocyclylalkyloxyoptionally substituted with the substituent group C, aromaticheterocyclylalkyloxy optionally substituted with the substituent groupC, non-aromatic heterocyclylalkyloxy optionally substituted with thesubstituent group C, aromatic carbocyclylamino optionally substitutedwith the substituent group C, non-aromatic carbocyclylamino optionallysubstituted with the substituent group C, aromatic heterocyclylaminooptionally substituted with the substituent group C, non-aromaticheterocyclylamino optionally substituted with the substituent group C),non-aromatic carbocyclyl optionally substituted with the substituentgroup H (the substituent group G, oxo), aromatic heterocyclyl optionallysubstituted with the substituent group G, non-aromatic heterocyclyloptionally substituted with the substituent group H, aromaticcarbocyclylamino optionally substituted with the substituent group G,non-aromatic carbocyclylamino optionally substituted with thesubstituent group H, aromatic heterocyclylamino optionally substitutedwith the substituent group G, non-aromatic heterocyclylamino optionallysubstituted with the substituent group H, amino optionally substitutedwith the substituent group I (hydroxy, cyano, alkyl, haloalkyl,alkylsulfonyl, haloalkylsulfonyl), or

a group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein R^(2a) is each independently a hydrogen atom, halogen, alkyloptionally substituted with the substituent group J (halogen, hydroxy,non-aromatic carbocyclyl optionally substituted with halogen), alkyloxyoptionally substituted with the substituent group J,R^(2b) is each independently a hydrogen atom, halogen, alkyl optionallysubstituted with the substituent group J, alkyloxy optionallysubstituted with the substituent group J, orR^(2a) and R^(2b) which are attached to the same carbon atom at any oneposition may be taken together to form oxo, or non-aromatic carbocyclyloptionally substituted with halogen; R^(2c) is aromatic carbocyclyloptionally substituted with the substituent group G, non-aromaticcarbocyclyl optionally substituted with the substituent group H,aromatic heterocyclyl optionally substituted with the substituent groupG, non-aromatic heterocyclyl optionally substituted with the substituentgroup H, aromatic carbocyclyloxy optionally substituted with thesubstituent group G, non-aromatic carbocyclyloxy optionally substitutedwith the substituent group H, aromatic heterocyclyloxy optionallysubstituted with the substituent group G, non-aromatic heterocyclyloxyoptionally substituted with the substituent group H, aromaticcarbocyclylamino optionally substituted with the substituent group G,non-aromatic carbocyclylamino optionally substituted with thesubstituent group H, aromatic heterocyclylamino optionally substitutedwith the substituent group G, non-aromatic heterocyclylamino optionallysubstituted with the substituent group H, aromatic carbocyclylsulfonyloptionally substituted with the substituent group G, non-aromaticcarbocyclylsulfonyl optionally substituted with the substituent group H,aromatic heterocyclylsulfonyl optionally substituted with thesubstituent group G, or non-aromatic heterocyclylsulfonyl optionallysubstituted with the substituent group H;n is an integer from 1 to 3 (hereinafter referred to as r2′-4),

the compound wherein R² is aromatic carbocyclyl optionally substitutedwith the substituent group G, non-aromatic carbocyclyl optionallysubstituted with the substituent group H, aromatic heterocyclyloptionally substituted with the substituent group G, non-aromaticheterocyclyl optionally substituted with the substituent group H, or

a group represented by the following formula: —(CR^(2a)R^(2b))—R^(2c)wherein R^(2a) and R^(2b) are each independently a hydrogen atom,halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, orR^(2a) and R^(2b) which are attached to the same carbon atom at any oneposition may be taken together to form non-aromatic carbocyclyloptionally substituted with halogen;R^(2c) is aromatic carbocyclyl optionally substituted with thesubstituent group G, non-aromatic carbocyclyl optionally substitutedwith the substituent group H, aromatic heterocyclyl optionallysubstituted with the substituent group G, non-aromatic heterocyclyloptionally substituted with the substituent group H (hereinafterreferred to as r2′-5),

the compound wherein R² is aromatic carbocyclyl optionally substitutedwith the substituent group G, non-aromatic carbocyclyl optionallysubstituted with the substituent group H, aromatic heterocyclyloptionally substituted with the substituent group G, non-aromaticheterocyclyl optionally substituted with the substituent group H(hereinafter referred to as r2′-6),

the compound wherein R² is a group represented by the following formula:—(CR^(2a)R^(2b))—R^(2c)

wherein R^(2a) and R^(2b) are each independently a hydrogen atom;R^(2c) is substituted or unsubstituted aromatic carbocyclyl, substitutedor unsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl (hereinafter referred to as r2′-7),

(10) the compound wherein R³ is substituted or unsubstituted alkyl(hereinafter referred to as r3′-1),

the compound wherein R³ is hydroxyalkyl, cyanoalkyl, alkyl optionallysubstituted with trialkylsilylalkyloxy, aromatic carbocyclylalkyloptionally substituted with halogen, non-aromatic carbocyclylalkyl,aromatic heterocyclylalkyl, non-aromatic heterocyclylalkyl (hereinafterreferred to as r3′-2),

(11) the compound wherein R⁴ is a hydrogen atom, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted carbamoyl, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, orsubstituted or unsubstituted aromatic heterocyclyl (hereinafter referredto as r4′-1),

the compound wherein R⁴ is a hydrogen atom, alkyl, haloalkyl,hydroxyalkyl, alkenyl optionally substituted with aromatic carbocyclyl,carbamoyl optionally substituted with the substituent group F, aromaticcarbocyclyl optionally substituted with the substituent group C,non-aromatic carbocyclyl optionally substituted with the substituentgroup C, aromatic heterocyclyl optionally substituted with thesubstituent group C, or non-aromatic heterocyclyl optionally substitutedwith the substituent group C (hereinafter referred to as r4′-2),

the compound wherein R⁴ is a hydrogen atom, alkyl, haloalkyl, oraromatic heterocyclyl optionally substituted with the substituent groupC (hereinafter referred to as r4′-3),

(12) the compound wherein R⁵ is a hydrogen atom, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkylcarbonyl, substituted or unsubstitutedalkyloxycarbonyl, or substituted or unsubstituted carbamoyl (hereinafterreferred to as r5′-1),

the compound wherein R⁵ is a hydrogen atom, halogen, alkyl optionallysubstituted with the substituent group K (halogen, hydroxy, cyano,alkyl, haloalkyl, hydroxyalkyl, alkylsulfonyl, haloalkylsulfonyl, aminooptionally substituted with the substituent group C, carbamoyloptionally substituted with the substituent group F, non-aromaticheterocyclyl optionally substituted with the substituent group C),carbamoyl optionally substituted with the substituent group L (alkyl,haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl), alkenyl,haloalkenyl, alkylcarbonyl, haloalkylcarbonyl, alkyloxycarbonyl(hereinafter referred to as r5′-2),

the compound wherein R⁵ is a hydrogen atom, alkyl, haloalkyl,hydroxyalkyl, alkenyl, alkylcarbonyl, haloalkylcarbonyl, alkylcarbamoyl,hydroxyalkylcarbamoyl, alkylaminoalkylcarbamoyl or alkylaminoalkyl(hereinafter referred to as r⁵-3),

(13) the compound wherein R⁶ is a hydrogen atom, halogen, hydroxy,amidino, guanidino, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkylcarbonyl, orsubstituted or unsubstituted carbamoyl (hereinafter referred to asr6′-1),

the compound wherein R⁶ is a hydrogen atom, halogen, hydroxy, guanidino,alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkylcarbonyl, carbamoyloptionally substituted with the substituent group M (hydroxy, cyano,alkyl, haloalkyl, hydroxyalkyl, alkylaminoalkyl, alkyloxy, haloalkyloxy,alkylsulfonyl, haloalkylsulfonyl) (hereinafter referred to as r6′-2),

the compound wherein R⁶ is a hydrogen atom, halogen, alkyl, haloalkyl,hydroxyalkyl, alkenyl, carbamoyl, or alkylcarbamoyl (hereinafterreferred to as r6′-3).

The compounds of formula (I), formula (II) or formula (III) are notlimited to specific isomers but include all possible isomers (e.g.,keto-enol isomers, imine-enamine isomers, diastereoisomers, enantiomers,rotamers or the like), racemates or mixtures thereof.

One or more hydrogen, carbon and/or other atom(s) in the compounds offormula (I), formula (II) or formula (III) may be replaced with isotopesof hydrogen, carbon and/or other atoms respectively. Examples ofisotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur,fluorine, iodine and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ¹²³I and ³⁶Cl respectively. The compounds offormula (I), formula (II) or formula (III) include the compoundsreplaced with these isotopes. The compounds replaced with the aboveisotopes are useful as medicines and include all of radiolabeledcompounds of the compound of formula (I), formula (II) or formula (III).A “method of radiolabeling” in the manufacture of the “radiolabeledcompounds” is encompassed by the present invention, and the“radiolabeled compounds” are useful for studies on metabolized drugpharmacokinetics, studies on binding assay and/or diagnostic tools.

A radiolabeled compound of the compounds of formula (I), formula (II) orformula (III) can be prepared using well-known methods in this field ofthe invention. For example, a tritium-labeled compound of formula (I),formula (II) or formula (III) can be prepared by introducing a tritiumto a certain compound of formula (I), formula (II) or formula (III),through a catalytic dehalogenation reaction using a tritium. This methodcomprises reacting with an appropriately-halogenated precursor of thecompound of formula (I), formula (II) or formula (III) with tritium gasin the presence of an appropriate catalyst, such as Pd/C, and in thepresence or absent of a base. The other appropriate method of preparinga tritium-labeled compound can be referred to “Isotopes in the Physicaland Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6(1987)”. A ¹⁴C-labeled compound can be prepared by using a raw materialhaving ¹⁴C.

The pharmaceutically acceptable salts of the compounds of formula (I),formula (II) or formula (III) include, for example, salts with alkalinemetal (e.g., lithium, sodium, potassium or the like), alkaline earthmetal (e.g., calcium, barium or the like), magnesium, transition metal(e.g., zinc, iron or the like), ammonia, organic bases (e.g.,trimethylamine, triethylamine, dicyclohexylamine, ethanolamine,diethanolamine, triethanolamine, meglumine, diethanolamine,ethylenediamine, pyridine, picoline, quinoline or the like), salts withamino acids, or salts with inorganic acids (e.g., hydrochloric acid,sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoricacid, hydroiodic acid or the like) or organic acids (e.g., formic acid,acetic acid, propionic acid, trifluoroacetic acid, citric acid, lacticacid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelicacid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbicacid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonicacid, ethanesulfonic acid or the like). Especially, salts withhydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid,methanesulfonic acid and the like are included. These salts can beformed by the usual methods.

The compounds of formula (I), formula (II) or formula (III) of thepresent invention or pharmaceutically acceptable salts thereof may formsolvates (e.g., hydrates or the like) and/or crystal polymorphs. Thepresent invention encompasses those various solvates and crystalpolymorphs. “Solvates” may be those wherein any numbers of solventmolecules (e.g., water molecules or the like) are coordinated with thecompounds of formula (I), formula (II) or formula (III). When thecompounds of formula (I), formula (II) or formula (III) orpharmaceutically acceptable salts thereof are allowed to stand in theatmosphere, the compounds may absorb water, resulting in attachment ofadsorbed water or formation of hydrates. Recrystallization of thecompounds of formula (I), formula (II) or formula (III) orpharmaceutically acceptable salts thereof may produce crystalpolymorphs.

The compounds of formula (I), formula (II) or formula (III) of thepresent invention or pharmaceutically acceptable salts thereof may formprodrugs. The present invention also encompasses such various prodrugs.Prodrugs are derivatives of the compounds of the present invention thathave chemically or metabolically degradable groups, and compounds thatare converted to the pharmaceutically active compounds of the presentinvention through solvolysis or under physiological conditions in vivo.Prodrugs include compounds that are converted to the compounds offormula (I), formula (II) or formula (III) through enzymatic oxidation,reduction, hydrolysis or the like under physiological conditions invivo, compounds that are converted to the compounds of formula (I),formula (II) or formula (III) through hydrolysis by gastric acid etc.,and the like. Methods for selecting and preparing suitable prodrugderivatives are described in, for example, “Design of Prodrugs,Elsevier, Amsrdam, 1985”. Prodrugs themselves may have some activity.

When the compounds of formula (I), formula (II) or formula (III) orpharmaceutically acceptable salts thereof have hydroxyl group(s),prodrugs include acyloxy derivatives and sulfonyloxy derivatives thatare prepared by, for example, reacting compounds having hydroxylgroup(s) with suitable acyl halide, suitable acid anhydride, suitablesulfonyl chloride, suitable sulfonyl anhydride and mixed anhydride, orwith a condensing agent. For example, they include CH₃COO—, C₂H₅COO—,tert-BuCOO—, C₁₅H₃₁COO—, PhCOO—, (m-NaOOCPh)COO—, NaOOCCH₂CH₂COO—,CH₃CH(NH₂)COO—, CH₂N(CH₃)₂COO—, CH₃SO₃—, CH₃CH₂SO₃—, CF₃SO₃—, CH₂FSO₃—,CF₃CH₂SO₃—, p-CH₃O-PhSO₃—, PhSO₃— and p-CH₃PhSO₃.

General procedures for the synthesis of the compounds of the presentinvention are described below. Starting materials and reaction reagentsused in such synthesis are commercially available or can be synthesizedaccording to methods well known in the art using compounds commerciallyavailable.

For example, the compounds of the present invention represented byformula (I), formula (II) or formula (III) can be synthesized inaccordance with the synthetic methods as described below.

wherein R¹, R⁵, R⁶, X, Z and W are the same as the above 17); R² issubstituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, or a group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein each symbol in the formula is the same as the above 17).

Step 1

The compound a2 can be synthesized by the reaction of the compound a1,which is commercially available or can be synthesized according to theknown methods, with a brominating agent.

The reaction temperature is −20° C. to the reflux temperature,preferably 25° C. to the reflux temperature.

The reaction time is 0.1 to 12 hours, preferably 0.5 to 8 hour(s).

As the brominating agent, pyridinium tribromide, tetrabutylammoniumbromide, bromide and the like are exemplified, and 1 to 2 moleequivalent(s) can be used per an equivalent of the compound a1.

As the reaction solvent, dichloromethane, chloroform and the like areexemplified.

Step 2

The compound A1 can be synthesized by the reaction of the compound a2with the compound a3.

The reaction temperature is 0° C. to the reflux temperature, preferably10° C. to the reflux temperature.

The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hour(s).

1 to 2 mole equivalent(s) of the compound a3 can be used per anequivalent of the compound a2.

As the reaction solvent, methanol, ethanol, THF, DMF and the like areexemplified.

wherein R¹, R², R⁵, R⁶, X, W and Z are the same as the above 17). Thecompound A2 can be synthesized by the reaction of the compound a4, whichis the compound wherein R² in the compound A1 is a hydrogen atom, withthe compound a5 in the presence of a condensation agent and a base.

1 to 3 mole equivalent(s) of the compound a5 can be used per anequivalent of the compound a4.

As the condensation agent, dicyclohexyl carbodiimide,carbonyldiimidazole, dicyclohexyl carbodiimide-N-hydroxybenzotriazole,EDC, 4-(4, 6-dimethoxy-1,3,5,-triazine-2-yl)-4-methyl morpholiniumchloride, HATU and the like are exemplified, and 1 to 5 moleequivalent(s) can be used per an equivalent of the compound a4.

As the base, DIEA, triethylamine, pyridine and the like are exemplified,and 1 to 5 mole equivalent(s) can be used per an equivalent of thecompound a4.

The reaction temperature is −20° C. to 100° C., preferably 0° C. to 80°C.

The reaction time is 0.1 to 24 hours, preferably 1 to 12 hour(s).

As the reaction solvent, DMF, DMA, NMP, THF, dioxane, dichloromethane,acetonitrile, pyridine and the like are exemplified. The reactionsolvent may be used alone or in combination.

In addition, the compound A2 can also be synthesized by using the acidhalide or the acid sulfonyl compound. The acid halide can be synthesizedby the reaction of the compound a5 with a halogenating agent, and theacid sulfonyl compound can be synthesized by the reaction of thecompound a5 with a sulfonylating agent in the presence of a base such astriethylamine, pyridine and the like. The compound A2 can be synthesizedby the reaction of the acid halide or the acid sulfonyl compoundobtained thereby with the compound a4 in the presence of a base.

In the reaction of synthesis of the acid halide or the acid sulfonylcompound, as the halogenating agent, thionyl chloride, phosphorusoxychloride, tetrabromomethane-triphenylphosphine and the like areexemplified, and 1 to 5 mole equivalent(s) can be used per an equivalentof the compound a5.

As the sulfonylating agent, methanesulfonyl chloride, p-toluenesulfonylchloride and the like are exemplified, and 1 to 5 mole equivalent(s) canbe used per an equivalent of the compound a5.

The reaction temperature is −80° C. to 50° C., preferably −20° C. to 20°C.

The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).

As the reaction solvent, acetonitrile, THF, toluene, dichloromethane andthe like can be used.

In the reaction of the acid halide or the acid sulfonyl compound withthe compound a4, 1 to 3 mole equivalent(s) of the acid halide or theacid sulfonyl compound can be used per an equivalent of the compound a4.

As the base, DIEA, potassium carbonate, sodium hydrogen carbonate,sodium hydride, sodium hydroxide, pyridine and the like are exemplified.

The reaction temperature is 0° C. to 150° C., preferably 20° C. to 100°C.

The reaction time is 0.5 to 120 hour(s), preferably 1 to 72 hours.

As the reaction solvent, acetonitrile, THF, toluene, dichloromethane,pyridine, DMF and the like are exemplified.

wherein R¹, R^(1a), R^(1b), R⁵, R⁶, X, Z, W and m are the same as theabove 17); X² is a protecting group of carboxy; R² is substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, ora group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein each symbol in the formula is the same as the above 17).

Step 1

The compound a7 can be synthesized by the reaction of the compound a2with the compound a6.

The reaction temperature is 0° C. to the reflux temperature, preferably10° C. to the reflux temperature.

The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).

1 to 2 mole equivalent(s) of the compound a6 can be used per anequivalent of the compound a2.

As the reaction solvent, methanol, ethanol, THF, DMF and the like areexemplified.

Step 2

The compound a8 can be synthesized by the hydrolysis of the compound a7under basic conditions.

The reaction temperature is 0° C. to 40° C., preferably 0° C. to 20° C.

The reaction time is 0.5 to 12 hour(s), preferably 1 to 6 hour(s).

As the base, lithium hydroxide, sodium hydroxide, potassium hydroxideand the like can be used, and 1 to 3 mole equivalent(s) can be used peran equivalent of the compound a7.

As the reaction solvent, methanol, ethanol, water, acetonitrile, THF andthe like are exemplified. The reaction solvent may be used alone or incombination.

Step 3

The compound A3 can be synthesized by the reaction of the compound a8with the compound a9 in the presence of a condensation agent and a base.

1 to 3 mole equivalent(s) of the compound a9 can be used per anequivalent of the compound a8.

As the condensation agent, dicyclohexyl carbodiimide,carbonyldiimidazole, dicyclohexyl carbodiimide-N-hydroxybenzotriazole,EDC, 4-(4, 6-dimethoxy-1,3,5,-triazine-2-yl)-4-methyl morpholiniumchloride, HATU and the like are exemplified, and 1 to 5 moleequivalent(s) can be used per an equivalent of the compound a8.

As the base, DIEA, triethylamine, pyridine and the like are exemplified.

The reaction temperature is −20° C. to 100° C., preferably 0° C. to 80°C.

The reaction time is 0.1 to 24 hour(s), preferably 1 to 12 hour(s).

As the reaction solvent, DMF, DMA, NMP, THF, dioxane, dichloromethane,acetonitrile, pyridine and the like are exemplified. The reactionsolvent may be used alone or in combination.

wherein R¹, R^(1a), R^(1b), R⁵, R⁶, X, Z, and W are the same as theabove 17); 1 is an integer from 0 to 2; X² is the same as theabove-mentioned; X³ is a leaving group; R² is substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, ora group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein each symbol in the formula is the same as the above 17).

Step 1

The compound all can be synthesized by the reaction of the compound a10with a reducing agent.

As the reducing agent, sodium borohydride, lithium borohydride, lithiumaluminium hydride and the like are exemplified, and 1 to 5 moleequivalent(s) can be used per an equivalent of the compound a10.

The reaction temperature is −20° C. to the reflux temperature,preferably 0° C. to 30° C.

The reaction time is 0.1 to 48 hour(s), preferably 0.5 to 24 hour(s).

As the reaction solvent, methanol, ethanol, propanol, isopropanol,butanol, THF, diethyl ether, dichloromethane, water and the like areexemplified.

Step 2

The compound a12 can be synthesized by the reaction of the compound allwith a sulfonylating agent and/or a halogenating agent.

i) Synthesis of the Sulfonyl Compound

As the sulfonylating agent, methanesulfonyl chloride, p-toluenesulfonylchloride and the like are exemplified, and 1 to 5 mole equivalent(s) canbe used per an equivalent of the compound all. This reaction can becarried out in the presence of a base.

As the base, triethylamine, pyridine and the like are exemplified, and 1to 5 mole equivalent(s) can be used per an equivalent of the compoundall.

The reaction temperature is −20° C. to 50° C., preferably 0° C. to 30°C.

The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).

As the reaction solvent, acetonitrile, THF, toluene, dichloromethane andthe like can be used.

ii) Synthesis of the Halogenated Compound

The halogenated compound can be synthesized by the reaction of the abovesulfonyl compound with a halogenating agent under basic conditions.

As the halogenating agent, lithium chloride and the like areexemplified, and 1 to 5 mole equivalent(s) can be used per an equivalentof the compound all.

As the base, triethylamine, pyridine and the like are exemplified, and 2to 10 equivalents can be used per an equivalent of the compound a10.

The reaction temperature is −20° C. to 50° C., preferably 0° C. to 30°C.

The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).

As the reaction solvent, acetonitrile, THF, dichloromethane and the likeare exemplified. The reaction solvent may be used alone or incombination.

Step 3

The compound A4 can be synthesized by the reaction of the compound a12with the compound a9 in the presence of a base.

1 to 3 mole equivalent(s) of the compound a9 can be used per anequivalent of the compound a12.

As the base, sodium hydride, potassium carbonate, sodium carbonate,potassium bicarbonate, sodium hydrogen carbonate, potassium hydroxide,sodium hydroxide, cesium carbonate, cesium hydroxide and the like areexemplified, and 1 to 3 mole equivalent(s) can be used per an equivalentof the compound a12.

The reaction temperature is 0° C. to 100° C., preferably 0° C. to 80° C.

The reaction time is 0.1 to 24 hour(s), preferably 1 to 12 hour(s).

As the reaction solvent, DMF, DMA, NMP, THF, DMSO and the like areexemplified. The reaction solvent may be used alone or in combination.

wherein R¹, R^(1a), R^(1b), R⁵, R⁶, X, Z and W are the same as the above17); 1 is the same as the above-mentioned; R² is substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, ora group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein each symbol in the formula is the same as the above 17).

The compound A5 can be synthesized by the reaction of the compound a12with the compound a13 in the presence of a base.

1 to 3 mole equivalent(s) of the compound a13 can be used per anequivalent of the compound a12.

As the base, sodium hydride, potassium carbonate, sodium carbonate,potassium bicarbonate, sodium hydrogen carbonate, potassium hydroxide,sodium hydroxide, cesium carbonate, cesium hydroxide and the like areexemplified, and 1 to 3 mole equivalent(s) can be used per an equivalentof the compound a12.

The reaction temperature is 0° C. to 100° C., preferably 0° C. to 80° C.

The reaction time is 0.1 to 24 hour(s), preferably 1 to 12 hour(s).

As the reaction solvent, DMF, DMA, NMP, THF, DMSO and the like areexemplified. The reaction solvent may be used alone or in combination.

wherein R¹, R⁵, R⁶, X, Z and W are the same as the above 17); R² issubstituted or unsubstituted alkyl, substituted or unsubstitutedaromatic carbocyclyl, substituted or unsubstituted non-aromaticcarbocyclyl, substituted or unsubstituted aromatic heterocyclyl,substituted or unsubstituted non-aromatic heterocyclyl.

The compound A6 can be synthesized by the condensation reaction of thecompound a4 and the cyanide a14 in the presence or absence of a base.

1 to 5 mole equivalent(s) of the compound a14 can be used per anequivalent of the compound a4.

As the base, sodium hydride, n-butyllithium, lithium diisopropylamideand the like are exemplified, and 1 to 5 equivalent(s) can be used peran equivalent of the compound a4.

The reaction temperature is 0° C. to the reflux temperature of thesolvent, preferably 30° C. to the reflux temperature of the solvent.

The reaction time is 0.5 to 24 hour(s), preferably 0.5 to 6 hour(s).

As the reaction solvent, THF, DMA, NMP and the like are exemplified. Thereaction solvent may be used alone or in combination.

wherein R¹, R⁵, R⁶, Z and W are the same as the above 17); R² issubstituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, or a group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein each symbol in the formula is the same as the above 17).

Step 1

The amido compound can be synthesized by the reaction of the compound b1with the compound b2 in the presence of a condensation agent and a base.

1 to 3 mole equivalent(s) of the compound b2 can be used per anequivalent of the compound b1.

As the condensation agent, dicyclohexyl carbodiimide,carbonyldiimidazole, dicyclohexyl carbodiimide-N-hydroxybenzotriazole,EDC, 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methyl morpholiniumchloride, HATU and the like are exemplified, and 1 to 5 moleequivalent(s) can be used per an equivalent of the compound b1.

As the base, DIEA, triethylamine, pyridine and the like are exemplified,and 1 to 5 mole equivalent(s) can be used per an equivalent of thecompound b1.

The reaction temperature is −20° C. to 100° C., preferably 0° C. to 80°C.

The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours.

As the reaction solvent, DMF, DMA, NMP, THF, dioxane, dichloromethane,acetonitrile, pyridine and the like are exemplified. The reactionsolvent may be used alone or in combination.

Step 2

The compound B1 can be synthesized by the reaction of the amido compoundobtained thereby with hydrazine.

1 to 5 mole equivalent(s) of hydrazine can be used per an equivalent ofthe compound b1.

The reaction temperature is −20° C. to 100° C., preferably 0° C. to 80°C.

The reaction time is 0.1 to 48 hour(s), preferably 1 to 24 hour(s).

wherein R², R⁵, R⁶, Z and W are the same as the above 17).

Step 1

The acid halide can be synthesized by the reaction of the compound b1with a halogenating agent, and the acid sulfonyl compound can besynthesized by the reaction of the compound b1 with a sulfonylatingagent in the presence of a base such as triethylamine, pyridine and thelike.

As the halogenating agent, thionyl chloride, phosphorus oxychloride,tetrabromomethane-triphenylphosphine and the like are exemplified, and 1to 5 mole equivalent(s) can be used per an equivalent of the compoundb1.

As the sulfonylating agent, methanesulfonyl chloride, p-toluenesulfonylchloride and the like are exemplified, and 1 to 5 mole equivalent(s) canbe used per an equivalent of the compound b1.

The reaction temperature is −80° C. to 50° C., preferably −20° C. to 20°C.

The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).

As the reaction solvent, acetonitrile, THF, toluene, dichloromethane andthe like can be used.

Step 2

The compound b3 can be synthesized by the reaction of the acid halide orthe acid sulfonyl compound obtained thereby with aminoguanidine in thepresence of a base.

1 to 5 mole equivalent(s) of aminoguanidine can be used per anequivalent of the compound b1.

As the base, DIEA, potassium carbonate, sodium hydrogen carbonate,sodium hydride, sodium hydroxide and the like are exemplified, and 1 to5 mole equivalent(s) can be used per an equivalent of the compound b1.

The reaction temperature is 0° C. to 150° C., preferably 20° C. to 100°C.

The reaction time is 0.5 to 120 hour(s), preferably 1 to 72 hour(s).

As the reaction solvent, acetonitrile, THF, toluene, dichloromethane,pyridine and the like are exemplified.

Step 3

The compound b4 can be synthesized by heating the compound b3 under highdilution conditions.

The reaction temperature is 50° C. to 100° C., preferably 70° C. to 100°C.

The reaction time is 0.1 to 24 hour(s), preferably 1 to 12 hour(s).

As the reaction solvent, water, ethanol, isopropanol and the like areexemplified. The reaction solvent may be used alone or in combination.

Step 4

The compound B2 can be synthesized by the reaction of the compound b4with the compound b5 in the same way as the step 3 in general proceduresfor the synthesis of the compound A3.

wherein R¹, R², R⁵, R⁶, Z and W are the same as the above 17).

The compound B3 can be synthesized by the reaction of the compound b6,which is the compound wherein R² in the compound B1 is a hydrogen atom,with the compound b5 in the same way as the step 3 in general proceduresfor the synthesis of the compound A3.

wherein R¹, R⁵, R⁶, Z and W are the same as the above 17); X² is thesame as the above-mentioned; R² is substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, substituted orunsubstituted non-aromatic heterocyclyl, or a group represented by thefollowing formula: —(CR^(2a)R^(2b))_(n)—R^(2c)wherein each symbol in the formula is the same as the above 17).

Step 1

The compound b8 can be synthesized by the reaction of the compound b1with the compound b7 in the presence of a base.

1 to 2 mole equivalent(s) of the compound b7 can be used per anequivalent of the compound b1.

As the base, DIEA, triethylamine, sodium carbonate, potassium carbonateand the like are exemplified, and 1 to 5 mole equivalent(s) can be usedper an equivalent of the compound b1.

The reaction temperature is −20° C. to 50° C., preferably −20° C. to 30°C.

The reaction time is 0.1 to 24 hour(s), preferably 1 to 12 hour(s).

As the reaction solvent, THF and the like are exemplified.

Step 2

The compound b10 can be synthesized by the reaction of the compound b8with the compound b9 in the presence of a base.

1 to 5 mole equivalent(s) of the compound b9 can be used per anequivalent of the compound b8.

As the base, DIEA, potassium carbonate, sodium hydrogen carbonate,sodium hydride, sodium hydroxide and the like are exemplified, and 1 to5 mole equivalent(s) can be used per an equivalent of the compound b8.

The reaction temperature is 0° C. to 150° C., preferably 20° C. to 100°C.

The reaction time is 0.5 to 120 hour(s), preferably 1 to 72 hour(s).

As the reaction solvent, acetonitrile, THF, toluene, dichloromethane,pyridine and the like are exemplified.

Step 3

The compound b11 can be synthesized by heating the compound b10 underhigh dilution conditions.

The reaction temperature is 50° C. to 200° C., preferably 100° C. to200° C.

The reaction time is 0.1 to 24 hour(s), preferably 1 to 12 hour(s).

As the reaction solvent, water, ethanol, isopropanol, xylene and thelike are exemplified. The reaction solvent may be used alone or incombination.

Step 4

The compound b12 can be synthesized by the hydrolysis of the compoundb11 in the same way as the step 2 in general procedures for thesynthesis of the compound A3.

Step 5

The compound B4 can be synthesized by the reaction of the compound b12with the compound b13 in the same way as the step 3 in generalprocedures for the synthesis of the compound A3.

wherein R¹, R⁵, R⁶, Z and W are the same as the above 17); R² issubstituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, or a group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein each symbol in the formula is the same as the above 17).

Step 1

The compound c2 can be synthesized by the reaction of the compound c1with hydroxylamine or the salt thereof in the presence of a base.

1 to 5 mole equivalent(s) of hydroxylamine or the salt thereof can beused per an equivalent of the compound c1.

As the base, DIEA, triethylamine, sodium carbonate, potassium carbonateand the like are exemplified, and 1 to 5 mole equivalent(s) can be usedper an equivalent of the compound c1.

The reaction temperature is −20° C. to 100° C., preferably 0° C. to 80°C.

The reaction time is 0.1 to 24 hour(s), preferably 1 to 12 hour(s).

As the reaction solvent, methanol, ethanol, water and the like areexemplified. The reaction solvent may be used alone or in combination.

Step 2

The compound c3 can be synthesized by the reaction of the compound c2with trichloroacetic anhydride in the presence of a base.

1 to 5 mole equivalent(s) of trichloroacetic anhydride can be used peran equivalent of the compound c2.

As the base, DIEA, triethylamine, pyridine and the like are exemplified,and 1 to 5 mole equivalent(s) can be used per an equivalent of thecompound c2.

The reaction temperature is −20° C. to the reflux temperature,preferably 0° C. to the reflux temperature.

The reaction time is 0.1 to 24 hour(s), preferably 1 to 12 hour(s).

As the reaction solvent, toluene, xylene and the like are exemplified.

Step 3

The compound C1 can be synthesized by the reaction of the compound c3with the compound c4.

1 to 100 equivalent(s) of the compound c4 can be used per an equivalentof the compound c3.

The reaction temperature is −20° C. to the reflux temperature,preferably 0° C. to the reflux temperature.

The reaction time is 0.1 to 24 hour(s), preferably 1 to 12 hour(s).

As the reaction solvent, DMF, DMA, NMP and the like are exemplified.

wherein R¹, R², R⁵, R⁶, Z and W are the same as the above 17).

The compound C2 can be synthesized by the reaction of the compound c5,which is the compound wherein R² in the compound C1 is a hydrogen atom,with the compound c6 in the same way as general procedures for thesynthesis of the compound A2.

wherein R¹, R⁵, R⁶, Z and W are the same as the above 17); X² is thesame as the above-mentioned; R² is a hydrogen atom, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, ora group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c) wherein each symbol in the formula is thesame as the above 17).

Step 1

The compound c8 can be synthesized by the reaction of the compound c2with the compound c7 in the presence of a base.

1 to 5 mole equivalent(s) of the compound c7 can be used per anequivalent of the compound c2.

As the base, DIEA, triethylamine, pyridine and the like are exemplified,and 1 to 5 mole equivalent(s) can be used per an equivalent of thecompound c7.

The reaction temperature is −20° C. to the reflux temperature,preferably 0° C. to the reflux temperature.

The reaction time is 0.1 to 24 hour(s), preferably 1 to 12 hour(s).

As the reaction solvent, acetonitrile, toluene, xylene and the like areexemplified.

Step 2 and after

The compound C3 can be synthesized by the amidation after the hydrolysisof the compound c8 in the same way as the synthesis of the compound B4.

wherein R¹, R⁵, R⁶, Z and W are the same as the above 17); R² is ahydrogen atom, substituted or unsubstituted aromatic carbocyclyl,substituted or unsubstituted non-aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic heterocyclyl, or a group represented by the followingformula: —(CR^(2a)R^(2b))_(n)—R^(2c)wherein each symbol in the formula is the same as the above 17).

Step 1

The compound d3 can be synthesized by the reaction of the compound d1with the compound d2.

1 to 2 mole equivalent(s) of the compound d2 can be used per anequivalent of the compound d1.

The reaction temperature is −20° C. to the reflux temperature,preferably 20′C to the reflux temperature.

The reaction time is 0.1 to 24 hour(s), preferably 1 to 12 hour(s).

As the reaction solvent, ethanol, isopropanol, water and the like areexemplified. The reaction solvent may be used alone or in combination.

Step 2

The compound D1 can be synthesized by the reaction of the compound d3with the d4 which is boronic acid or boronate in the presence of a metalcatalyst and a base.

As the metal catalyst, palladium acetate,bis(dibenzylideneacetone)palladium,tetrakis(triphenylphosphine)palladium,bis(triphenylphosphine)palladium(II) dichloride,bis(tri-tert-butylphosphine)palladium, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride and the likeare exemplified, and 0.001 to 0.5 equivalents can be used per anequivalent of the compound d3.

As the base, lithium hydroxide, sodium hydroxide, potassium hydroxide,potassium tert-butoxide, sodium tert-butoxide, sodium carbonate,potassium carbonate, sodium hydrogen carbonate, sodium phosphate, sodiumhydrogen phosphate, potassium phosphate, potassium hydrogen phosphate,cesium fluoride and the like are exemplified, and 1 to 10 equivalent(s)can be used per an equivalent of the compound d3.

1 to 10 mole equivalent(s) of boronic acid or boronate d4 can be usedper an equivalent of the compound d3.

The reaction temperature is 20° C. to the reflux temperature of thesolvent. This reaction can be carried out under microwave irradiation atappropriate temperature, as needed.

The reaction time is 0.1 to 48 hour(s), preferably 0.5 to 12 hour(s).

As the reaction solvent, THF, toluene, DMF, dioxane, water and the likeare exemplified. The reaction solvent may be used alone or incombination.

wherein R¹, R², R⁵, R⁶, Z and W are the same as the above 17).

Step 1

The compound d6 can be synthesized by the reaction of the compound d5,which is the compound wherein R² in the compound d3 is a hydrogen atom,with Boc₂O in the presence of DMAP.

1 to 2 equivalent(s) of DMAP can be used per an equivalent of the d5.

The reaction temperature is −10° C. to 80° C., preferably 10° C. to 60°C.

The reaction time is 0.5 to 24 hour(s), preferably 1 to 12 hour(s).

As the reaction solvent, THF, dioxane, acetonitrile, water and the likeare exemplified. The reaction solvent may be used alone or incombination.

Step 2

The compound d7 can be synthesized by the reaction of the compound d6with the d4 which is boronic acid or boronate in the presence of a metalcatalyst and a base in the same way as the above step 2.

Step 3

The compound d8 can be synthesized by the deprotection of Boc group,i.e. the reaction of the compound d7 with acid or lewis acid.

As the acid, hydrochloric acid-ethyl acetate, hydrochloricacid-methanol, hydrochloric acid-dioxane, sulfuric acid, formic acid,trifluoroacetic acid and the like are exemplified. As the lewis acid,trimethylsilyl iodide, BBr₃, AlCl₃, BF₃ (Et₂O) and the like areexemplified, and 1 to 100 mole equivalent(s) can be used per anequivalent of the compound d7.

The reaction temperature is 0° C. to 60° C., preferably 0° C. to 30° C.

The reaction time is 0.5 to 12 hour(s), preferably 0.5 to 6 hour(s).

As the reaction solvent, methanol, ethanol, water, acetone,acetonitrile, dichloromethane and the like are exemplified. The reactionsolvent may be used alone or in combination.

Step 4

The compound D2 can be synthesized by the reaction of the compound d8with the compound d9 in the same way as step 3 in general procedures forthe synthesis of the compound A2.

wherein R¹, R⁵, R⁶, Z and W are the same as the above 17); X² is thesame as the above-mentioned; R² is a hydrogen atom, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, ora group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein each symbol in the formula is the same as the above 17).

Step 1

The compound d12 can be synthesized by the reaction of the compound d10with the compound d11.

1 to 2 mole equivalent(s) of the compound d11 can be used per anequivalent of the compound d10.

The reaction temperature is −20° C. to the reflux temperature,preferably 0° C. to the reflux temperature.

The reaction time is 0.1 to 24 hour(s), preferably 1 to 12 hour(s).

As the reaction solvent, toluene, xylene and the like are exemplified.

Step 2

The compound d14 can be synthesized by the reaction of the compound d12with the compound d13.

1 to 2 mole equivalent(s) of compound d13 can be used per an equivalentof the compound d12.

The reaction temperature is 0° C. to the reflux temperature, preferably30° C. to the reflux temperature.

The reaction time is 0.1 to 48 hour(s), preferably 1 to 24 hour(s).

As the reaction solvent, dichloroethane, toluene, xylene and the likeare exemplified.

Step 3 and after

The compound D3 can be synthesized by the amidation after the hydrolysisof the compound d14 in the same way as the synthesis of the compound B4.

The urea compound E1 and the sulfonamide compound E2 can be synthesizedby the following reaction of the amine compound a4, b6, c5 or d8 whichcan be synthesized according to the above procedures.

wherein R¹, R⁵, R⁶, X, Y, Z and W are the same as the above 17); R^(2x)and R^(2y) are each independently a hydrogen atom, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, substituted orunsubstituted non-aromatic heterocyclyl, or R^(2x), R^(2y) and thenitrogen atom which are attached to R^(2x) and R^(2y) may be takentogether to form substituted or unsubstituted non-aromatic heterocycle.

Step 1

The compound e2 can be synthesized by the reaction of the compound e1which is synthesized by the above general procedures with CDI.

1 to 2 mole equivalent(s) of CDI can be used per an equivalent of thecompound e1.

The reaction temperature is 20° C. to 100° C., preferably 50° C. to 80°C.

The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).

As the reaction solvent, DMF, DMA, NMP, THF, dioxane and the like areexemplified. The reaction solvent may be used alone or in combination.

Step 2

The compound E1 can be synthesized by the reaction of the compound e2with the compound e3.

1 to 5 mole equivalent(s) of the compound e3 can be used per anequivalent of the compound e2.

The reaction temperature is −20° C. to 100° C., preferably 0° C. to 80°C.

The reaction time is 0.1 to 24 hour(s), preferably 1 to 12 hour(s).

As the reaction solvent, DMF, DMA, NMP, THF, dioxane, dichloromethane,acetonitrile and the like are exemplified. The reaction solvent may beused alone or in combination.

wherein R¹, R⁵, R⁶, X, Y, Z and W are the same as the above 17); X³ is aleaving group; R² is a hydrogen atom, substituted or unsubstitutedaromatic carbocyclyl, substituted or unsubstituted non-aromaticcarbocyclyl, substituted or unsubstituted aromatic heterocyclyl,substituted or unsubstituted non-aromatic heterocyclyl, or a grouprepresented by the following formula: —(CR^(2a)R^(2b))_(n)—R^(2c)wherein each symbol in the formula is the same as the above 17).

The compound E2 can be synthesized by the reaction of the compound e1with the compound e4.

1 to 1.5 mole equivalent(s) of the compound e4 can be used per anequivalent of the compound e1. This reaction can be carried out in thepresence of 1 to 5 mole equivalent(s) of a base per an equivalent of thecompound e1.

As the base, DIEA, triethylamine, pyridine and the like are exemplified.

The reaction temperature is 0° C. to 150° C., preferably 0° C. to 30° C.

The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 1 hour(s).

As the reaction solvent, DMF, DMA, NMP, THF, dioxane, dichloromethaneand the like are exemplified. The reaction solvent may be used alone orin combination.

The amino compound E3 and the ether compound E4 can be synthesized bythe following reaction of the ester compound b11, c8 or d14 which can besynthesized according to the above procedures.

wherein R¹, R⁵, R⁶, X, Z and W are the same as the above 17); X² i aprotecting group of carboxy; X³ is a leaving group; R² is a hydrogenatom, substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, or a group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c)wherein each symbol in the formula is the same as the above 17).

The compound E3 and E4 can be synthesized by the reaction of thecompound e6 with the compound e7 or e8 after conversion of the compounde5 into the compound e6 in the same way as the synthesis of the compoundA4 and A5.

The compounds of formula (I), formula (II) or formula (III) of thepresent invention prepared by the above general procedures can bepurified by referring to the known methods (e.g., chromatography,recrystallization and the like).

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an effective amount of the compound of theinvention, in combination with a pharmaceutically acceptable carrier.

For use of the compound of the invention as a medicament, apharmaceutical composition can be prepared according to conventionalmethods, using pharmaceutically acceptable carriers well known in theart, such as excipients, binders, disintegrants, lubricants, colourants,flavors, surfactants, etc.

For the pharmaceutical composition of the invention to be administeredin the treatment of mammals including human, an appropriate unit dosageform may be selected depending on the purpose of the treatment and theroute of administration. Specifically, such unit dosage form includesoral formulations such as tablet, coated tablet, powder, granule,capsule, liquid, pill, suspension, emulsion, etc., and parenteralformulations such as injectable solution, suppository, ointment, patch,aerosol, etc. Such unit dosage form can be formulated according tomethods well known in the art.

The amount of the compound in a formulation can be varied depending onits dosage form, route for administration, dosing regimen, etc.

Route for administration of the pharmaceutical composition can bedetermined depending on dosage form, age, sex, body weight, severity ofthe disease, and other factors, etc., and may be selected from variousroutes such as oral, subcutaneous, transdermal, rectal, intranasal,buccal, etc.

Dose of the compound of the invention in a pharmaceutical composition ofthe invention can be determined depending on the choice of route foradministration, age, sex, body weight, severity of the disease, thecompound to be administered, and other factors, etc., and can begenerally from 0.05 to 1000 mg/kg/day, preferably from 0.1 to 10mg/kg/day, for oral administration to adults. For parenteraladministration, dose can be varied widely depending on its route butgenerally from 0.005 to 100 mg/kg/day, preferably from 0.01 to 1mg/kg/day. Such pharmaceutical composition of the invention may beadministered once a day or in several times at a divided dosage in aday.

Following examples illustrate the present invention in more detail,however, the present invention is not limited to these examples. In NMRdata shown in Examples and Reference Examples, not all measured peaksmay be described. The meaning of each abbreviation is as follows.

Me: methylEt: ethyln-: normalt-Bu: tert-butyli-Pr: isopropylCF₃: trifluoromethylPh: phenylBn: benzylAc: acetylMs: methansulfonylTs: para-toluenesulfonylBoc: tert-butoxycarbonylDMSO: dimethyl sulfoxideDMA: N,N-dimethyl acetamide

DMF: N,N-dimethylformamide

THF: tetrahydrofuran

NMP: N-methylpyrrolidone

CDI: 1-1′-carbonyldiimidazole

DIEA: N,N-diisopropylethylamine

Py: pyridineEt₃N: triethylamineTFA: trifluoroacetic acidEDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlorideEDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimideHATU: 2-(1H-7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate methanaminium)Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0)MsCl: methansulfonyl chlorideTsCl: para-toluenesulfonyl chloride

HPLC: High Performance Liquid Chromatography TLC: Thin LayerChromatography

Rac: racemic compound

“Wedged bond” and “dashed bond” in the chemical formula representconfiguration. The compounds with “Rac” in the chemical formula areracemic compounds that are specified in relative configuration, and thecompounds with “Abs” are compounds that have absolute configuration.

Reference Example 11

Step 1

To a solution of 2,4-dimethyl-5-acetylthiazole (1.50 g, 9.66 mmol) inchloroform (15 mL) was added pyridinium tribromide (4.64 g, 14.5 mmol),and the mixture was heated for 1.5 hours at reflux. After cooled, waterwas added to the reaction mixture, and the mixture was extracted withchloroform. The organic phase was washed by saturated sodium hydrogencarbonate aqueous solution and water, dried over anhydrous magnesiumsulfate, and evaporated. The residue was purified by silica-gel columnchromatography (hexane-ethyl acetate) to afford compound 2 (1.29 g,yield: 57%).

¹H-NMR (CDCl₃) δ: 2.73 (s, 6H), 4.21 (s, 2H).

Step 2

To a solution of compound 2 (1.29 g, 5.51 mmol) in ethanol (10 mL) wasadded thiourea (0.46 g, 6.06 mmol), and the mixture was heated for 3hours at reflux. After cooled, the reaction mixture was evaporated. Tothe residue were added water and ethyl acetate, and the mixture wasdivided into the organic phase and the aqueous phase. The resultingaqueous phase was added to potassium carbonate and adjusted to pH8-9,the precipitate was filtered, and the resulting solid was washed bywater and dried, to afford compound 3 (0.84 g, yield: 72%).

¹H-NMR (DMSO-d₆) δ: 2.45 (s, 3H), 2.55 (s, 3H), 6.63 (s, 1H), 7.15 (s,2H).

Reference Example 2

Step 1

A solution of compound 43 (7.74 g, 40.2 mmol) and ethyl2-aminothiooxamate (5.1 g, 38.3 mmol) in acetic acid (5 mL) was stirredat 80° C. for 10 minutes. After cooled to room temperature, saturatedsodium hydrogen carbonate aqueous solution was added to the reactionmixture and the mixture was extracted with ethyl acetate. The organicphase was washed by brine, dried over anhydrous magnesium sulfate, andevaporated. The residue was purified by silica-gel column chromatography(hexane-ethyl acetate) to afford compound 44 (4.27 g, yield: 41%).

¹H-NMR (CDCl₃) δ: 1.44 (6H, q, J=7.0 Hz), 2.67 (3H, s), 4.47 (4H, q,J=7.1 Hz), 4.51 (4H, q, J=7.1 Hz).

Step 2

To a solution of compound 44 (4.69 g, 17.3 mmol) in chloroform (47 mL)was added pyridinium tribromide (7.99 g, 22.5 mmol, purity: 90%), andthe mixture was stirred at room temperature for 80 minutes. The reactionmixture was evaporated, to the residue was added ethanol (47 mL), andthe residue was dissolved. To the resulting solution was addedN-Boc-thiourea (3.35 g, 19.0 mmol) and the mixture was stirred at roomtemperature for 30 minutes. To the reaction mixture were added water andsaturated sodium hydrogen carbonate aqueous solution and the mixture wasextracted with ethyl acetate. The organic phase was washed by brine,dried over anhydrous magnesium sulfate, and evaporated. The residue waspurified by silica-gel column chromatography (hexane-ethyl acetate) toafford compound 45 (3.56 g, yield: 48%).

¹H-NMR (CDCl₃) δ: 1.45 (6H, t, J=7.1 Hz), 1.54 (9H, s), 4.44-4.52 (4H,m), 8.11 (1H, br s), 8.42 (1H, s).

Step 3

To a solution of compound 45 (1 g, 2.34 mmol) in ethanol (10 mL) wasadded sodium borohydride (177 mg, 4.68 mmol) under ice-cooling, and themixture was heated to room temperature and stirred for 1 hour. To thereaction mixture were added 2.0 mmol/L hydrochloric acid aqueoussolution and saturated sodium hydrogen carbonate aqueous solution, andthe mixture was neutralized and extracted with ethyl acetate. Theorganic phase was washed by brine, dried over anhydrous magnesiumsulfate, and evaporated, to afford crude product (818 mg) of compound46.

Step 4

To a solution of compound 46 (818 mg, 2.12 mmol) in DMF (8 mL) wereadded imidazole (217 mg, 3.18 mmol) and tert-butyldiphenylchlorosilane(875 mg, 3.18 mmol), and the mixture was stirred at room temperature for1.5 hours under nitrogen atmosphere. To the reaction mixture was addedwater and the mixture was extracted with ethyl acetate. The organicphase was washed by water and brine, dried over anhydrous magnesiumsulfate, and evaporated. The residue was purified by silica-gel columnchromatography (hexane-ethyl acetate) to afford compound 47 (983 mg,2-step yield: 74%).

¹H-NMR (CDCl₃) δ: 1.14 (9H, s), 1.39 (3H, t, J=7.0 Hz), 1.56 (9H, s),4.42 (2H, q, J=6.8 Hz), 4.95 (2H, s), 7.38-7.45 (6H, m), 7.69 (4H, d,J=6.9 Hz), 7.99 (1H, s), 8.24 (1H, s).

Step 5

To a solution of compound 47 (983 mg, 1.58 mmol) in THF (10 mL)-methanol(0.128 mL, 3.15 mmol) was added lithium borohydrate (240 mg, 11.0 mmol)under ice-cooling and the mixture was heated to room temperature andstirred for 21.5 hours. To the reaction mixture were added hydrochloricacid and saturated sodium hydrogen carbonate aqueous solution, and themixture was neutralized and extracted with ethyl acetate. The organicphase was washed by brine, and dried over anhydrous magnesium sulfate,and evaporated, to afford crude product (831 mg) of compound 48. LC/MS(method 1) RT=3.11, [M+H]⁺=582.

Reference Example 3

As Step 1 in Example 12, compound 18 and ethyl oxamate were reacted toafford compound 49. As Reference Example 2, the resulting compound 49was reduced, and the hydroxyl group was protected to afford compound 50.LC/MS (method 9) RT=1.77, [M+H]⁺=246.

Reference Example 4

Step 1

Sodium hydride (1.28 g, 32 mmol) was dissolved in THF (15 mL) andstirred at 0° C. for 10 minutes. Compound 51 (3.85 g, 26.7 mmol) wasadded to reaction mixture and stirred at 0° C. for 10 minutes. To theresulting mixture was added 2, 2,2-trifluoroethyl-4-methylbenzenesulfonate (7.47 g, 29.4 mmol), and themixture was stirred at room temperature for 16 hours. To the reactionmixture were added ammonium chloride aqueous solution and extracted withethyl acetate. The organic phase was washed by brine, dried overanhydrous magnesium sulfate, and evaporated. The residue was purified bysilica-gel column chromatography (hexane-ethyl acetate) to affordcompound 52 (2.55 g, yield: 42%).

1H-NMR (CDCl₃) δ: 1.27 (3H, t, J=8.7 Hz), 2.06-2.07 (1H, m), 2.29-2.32(1H, m), 2.52-2.56 (2H, m), 2.99-3.06 (1H, m), 3.75 (1H, q, J=8.7 Hz),4.14-4.16 (2H, m), 4.29-4.36 (1H, m).

Step 2

To a solution of compound 52 (7.5 g, 28 mmol) in THF (20 mL) was addedsodium hydroxide aqueous solution (2 mol/L, 16 mL) at room temperature,and the mixture was stirred for 22 hours. To the reaction mixture wereadded hydrochloric acid (2 mol/L) and sodium chloride, and the mixturewas extracted with ethyl acetate. The organic phase was dried overanhydrous magnesium sulfate and evaporated. The residue was purified bysilica-gel column chromatography (hexane-ethyl acetate) to affordcompound 53 (1.25 g, yield: 56%, 1:1 mixture of cis-trans).

1H-NMR (CDCl₃) δ: 2.28-2.40 (4H, m), 2.57-2.60 (4H, m), 2.63-2.73 (1H,m), 3.04-3.11 (1H, m), 3.74-3.78 (4H, m), 4.01-4.08 (1H, m), 4.31-4.38(1H, m).

Reference Example 5

Step 1

To a solution of compound 54 (400 mg, 2.19 mmol) in 1,4-dioxane (8 mL)were added compound 55 (399 mg, 2.63 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (254 mg, 0.438 mmol) andcesium carbonate (2499 mg, 7.67 mmol) and degassed under nitrogenatmosphere. To the reaction mixture was addedbisbenzylideneacetonepalladium(0) (126 mg, 0.219 mmol) and the mixturewas stirred with heating under nitrogen atmosphere at 80° C. for 3hours. After cooled, to the reaction mixture was added water, theinsoluble matter was filtered, and the filtrate was extracted with ethylacetate. The organic phase was washed by water and brine, dried overanhydrous sodium sulfate, and evaporated. The residue was purified bysilica-gel column chromatography (hexane-ethyl acetate) to affordcompound 56 (424 mg, yield: 71%).

¹H-NMR (CDCl₃) δ: 3.55-3.63 (1H, m), 3.78 (3H, s), 4.35-4.43 (4H, m),8.48 (2H, s).

Step 2

To a solution of compound 56 (420 mg, 1.608 mmol) in THF (4.2 mL) wasadded 2.0 mmol/L sodium hydroxide aqueous solution (2.4 ml, 4.82 mmol),and the mixture was stirred at room temperature for 1 hour. To thereaction mixture was added 2.0 mmol/L hydrochloric acid aqueous solution(2.4 ml), and the mixture was neutralized and extracted with ethylacetate. The organic phase was washed by brine, dried over anhydroussodium sulfate, and evaporated, to afford crude product (380 mg) ofcompound 57.

LC/MS (method 1) RT=1.28, [M+H]⁺=248.

Example 1 Synthesis of Compound I-35

Step 1

A solution of compound 4 (525 mg, 2.29 mmol), sodiumtrifluoromethanesulfinate (1.07 g, 6.88 mmol) and potassium iodide (76.0mg, 0.458 mmol) in DMF (5 mL) was stirred at 120° C. for 15 minutes. Tothe reaction mixture was added water −2 mol/L hydrochloric acid and theprecipitate was filtered. The resulting solid was washed by water anddried over to afford compound 5 (580 mg, yield: 90%).

¹H-NMR (CDCl₃) δ: 3.70 (2H, s), 4.46 (2H, s), 7.34-7.43 (4H, m).

Step 2

To a solution of compound 3 (112 mg, 0.531 mmol), compound 5 (100 mg,0.354 mmol) and HATU (202 mg, 0.531 mmol) in DMA (2 mL) was added Et₃N(0.074 mL, 0.531 mmol), and the mixture was stirred at room temperaturefor 17.5 hours. To the reaction mixture was added sodium hydrogencarbonate aqueous solution, and the mixture was extracted with ethylacetate. The organic phase was washed by water and brine, dried overanhydrous magnesium sulfate, and evaporated. The residue was purified bysilica-gel column chromatography (hexane-ethyl acetate). The resultingsolid was suspended in diisopropyl ether and filtered to afford compoundI-35 (18.7 mg, yield: 11%).

¹H-NMR (CDCl₃) δ: 2.55 (3H, s), 2.65 (3H, s), 3.83 (2H, s), 4.49 (2H,s), 6.91 (1H, s), 7.39 (2H, d, J=8.4 Hz), 7.46 (2H, d, J=8.2 Hz), 8.85(1H, s).

Example 2 Synthesis of Compound I-37

To a suspension of 3-oxocyclopentanecarboxylic acid (2.00 g, 15.6 mmol),compound 3 (3.63 g, 17.2 mmol) and HATU (8.90 g, 23.4 mmol) in DMA (20mL) was added Et₃N (3.25 mL, 23.4 mmol), and the mixture was stirred atroom temperature for 17 hours. To the reaction mixture were added waterand saturated sodium hydrogen carbonate aqueous solution, and themixture was extracted with THF-ethyl acetate. The organic phase waswashed by water and brine, dried over anhydrous magnesium sulfate, andevaporated. The residue was purified by silica-gel column chromatography(hexane-ethyl acetate). The residue was suspended in dichloromethane,and solid was filtered. The filtrate was evaporated, the residue waspurified by silica-gel column chromatography (hexane-ethyl acetate), andthe resulting solid was suspended in diisopropyl ether and filtered, toafford I-37 (1.82 g, yield: 36%).

¹H-NMR (CDCl₃) δ: 2.17-2.39 (3H, m), 2.39-2.71 (3H, m), 2.58 (3H, s),2.67 (3H, s), 3.00-3.14 (1H, m), 6.95 (1H, s), 9.36 (1H, s).

Example 3 Synthesis of Compound I-39

To a solution of compound I-37 (150 mg, 0.467 mmol) in dichloromethane(3 mL) were added 2,2,2-trifluoroethaneamine (44 mL, 0.560 mmol), aceticacid (0.032 mL, 0.560 mmol) and sodium triacetoxyborohydride (198 mg,0.933 mmol), and the mixture was stirred at room temperature for 5hours. To the reaction mixture was added sodium hydrogen carbonateaqueous solution, and the mixture was extracted with ethyl acetate. Theorganic phase was washed by water and brine, dried over anhydrousmagnesium sulfate, and evaporated. The residue was purified bysilica-gel column chromatography (hexane-ethyl acetate) to afford I-39(149 mg, yield: 79%).

¹H-NMR (CDCl₃) δ: 1.50-2.36 (7H, m), 2.62 (3H, s), 2.71 (3H, s),3.00-3.54 (3.25H, m), 3.57-3.69 (0.75H, m), 6.92 (0.75H, s), 6.95(0.25H, s), 8.91 (0.25H, s), 11.32 (0.75H, s).

Example 4 Synthesis of I-56

Step 1

To a solution of compound I-37 (1.20 g, 3.73 mmol) in methanol (12mL)-THF (6 mL) was added sodium borohydride (212 mg, 5.60 mmol) underice-cooling, and the mixture was stirred at the same temperature for 90minutes. To the reaction mixture was added 2 mol/L hydrochloric acid andthen saturated sodium hydrogen carbonate aqueous solution, and themixture was extracted with ethyl acetate. The organic phase was washedby water and brine, dried over anhydrous magnesium sulfate, andevaporated. The residue was purified by silica-gel column chromatography(ethyl acetate-methanol). The resulting solid was suspended indiisopropyl ether and filtered to afford compound 6 (784 mg, yield:65%).

¹H-NMR (DMSO-d₆) δ: 1.49-2.03 (5H, m), 2.04-2.19 (1H, m), 2.59 (3H, s),2.83-3.00 (1H, m), 4.05-4.18 (1H, m), 4.68 (1H, d, J=4.2 Hz), 7.26 (1H,s), 12.20 (1H, s).

Step 2

To a solution of compound 6 (745 mg, 2.30 mmol) in Py(7.5 mL) was addedTsCl (659 mg, 3.46 mmol) at 0° C., and the mixture was stirred at roomtemperature for 19.5 hours. To the reaction mixture was added 2 mol/Lhydrochloric acid, and the mixture was adjusted to about pH4 andextracted with ethyl acetate. The organic phase was washed by water andbrine, dried over anhydrous magnesium sulfate, and evaporated. Theresidue was purified by silica-gel column chromatography (hexane-ethylacetate). The resulting solid was suspended in diethyl ether-ethylacetate and filtered to afford compound 7 (602 mg, yield: 55%).

¹H-NMR (CDCl₃) δ: 1.74-2.15 (4H, m), 2.15-2.28 (2H, m), 2.43 (3H, s),2.58 (3H, s), 2.67 (3H, s), 2.72-2.85 (1H, m), 4.99-5.08 (1H, m), 6.91(1H, s), 7.31 (2H, d, J=8.2 Hz), 7.80 (2H, d, J=8.1 Hz), 9.10 (1H, s).

Step 3

To a solution of compound 7 (300 mg, 0.628 mmol) in DMSO (3 mL) wereadded sodium cyanide (46.2 mg, 0.942 mmol) and 15-crown-5-ether (208 mg,0.942 mmol), and the mixture was stirred at 100° C. for 30 minutes. Thereaction mixture was cooled to room temperature, then to the mixture wasadded water, and the mixture was extracted with ethyl acetate. Theorganic phase was washed by water and brine, dried over anhydrousmagnesium sulfate, and evaporated. The residue was purified bysilica-gel column chromatography (hexane-ethyl acetate) to afford I-56(25.1 mg, yield: 12%).

¹H-NMR (CDCl₃) δ: 1.78-2.15 (4H, m), 2.15-2.30 (1H, m), 2.30-2.44 (1H,m), 2.58 (3H, s), 2.68 (3H, s), 2.80-2.94 (1H, m), 2.98-3.12 (1H, m),6.95 (1H, s), 10.16 (1H, s).

Example 5 Synthesis of Compound I-58

Step 1

Compound 8 (500 mg, 3.59 mmol) was dissolved in chloroform (10 mL). Tothe solution was added pyridinium bromide perbromide (purity: 90%) (1.66g, 4.67 mmol) under ice-cooling, and the mixture was heated for 3 hoursat reflux. The reaction mixture was evaporated, and the residue wasdissolved in ethanol (10 mL). To the reaction mixture was added thiourea(301 mg, 3.95 mmol), and the mixture was stirred at room temperature for2 hours. To the resulting mixture was added saturated sodium hydrogencarbonate aqueous solution, and the mixture was extracted with ethylacetate. The organic phase was washed by water and brine, dried overanhydrous magnesium sulfate, and evaporated. The residue was purified bysilica-gel column chromatography (hexane-ethyl acetate). The resultingoil was solidified by diisopropyl ether and filtered to afford compound9 (388 mg, yield: 55%).

¹H-NMR (CDCl₁) δ: 2.39 (3H, s), 2.46 (3H, s), 5.00 (2H, brs), 6.58 (1H,s).

Step 2

To a solution of 2-(2, 6-difluorophenyl)acetic acid (50.0 mg, 0.290mmol), compound 9 (62.4 g, 0.320 mmol) and Et₃N (0.060 mL, 0.436 mmol)in DMA (1 mL) was added HATU (166 mg, 0.436 mmol), and the mixture wasstirred at room temperature for 16 hours. To the reaction mixture wasadded sodium hydrogen carbonate aqueous solution, and the mixture wasextracted with ethyl acetate. The organic phase was evaporated, and theresidue was purified by silica-gel column chromatography (hexane-ethylacetate). The resulting solid was suspended in diisopropyl ether andfiltered to afford compound I-58 (21.0 mg, yield: 21%).

¹H-NMR (DMSO-d₆) δ: 2.38 (3H, s), 2.40 (3H, s), 3.91 (2H, s), 7.05-7.17(2H, m), 7.26 (1H, s), 7.34-7.47 (1H, m), 12.61 (1H, s).

Example 6 Synthesis of Compound I-59

Step 1

To a solution of compound 3 (229 mg, 1.08 mmol) in THF (6 mL)-DMF (2 mL)was added CDI (211 mg, 1.30 mmol), and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was stirred at 80° C. for50 minutes and stood at room temperature overnight. The reaction mixturewas stirred at 80° C. for 3 hours and cooled to room temperature. Theprecipitate was filtered, and the resulting solid was washed by THF toafford crude product of compound 10 (120 mg).

Step 2

To a suspension of crude product (40 mg) of compound 10 in DMF (1 mL)was added 4-bromo-N-methylaniline (29.2 mg, 0.157 mmol), and the mixturewas stirred at room temperature for 4.5 hours. To the reaction mixturewas added water, and the mixture was extracted with ethyl acetate. Theorganic phase was washed by water and brine, dried over anhydrousmagnesium sulfate, and evaporated. The residue was purified bysilica-gel column chromatography (hexane-ethyl acetate). The resultingsolid was suspended in diisopropyl ether and filtered to afford compoundI-59 (19.0 mg, yield: 34%).

¹H-NMR (CDCl₃) δ: 2.53 (3H, s), 2.64 (3H, s), 3.37 (3H, s), 6.83 (1H,s), 7.18-7.24 (2H, m), 7.61-7.68 (2H, m), 7.77 (1H, brs).

Example 7 Synthesis of Compound I-65

Step 1

To a solution of compound 3 (14.1 g, 66.7 mmol) in dichloromethane (140mL)-acetic acid (70 mL) was added iodine monochloride (12 g, 73.3 mmol)at 0° C., and the mixture was stirred at room temperature for 1 hour. Toice-0.5 mol/L sodium carbonate aqueous solution was added the reactionmixture, and the mixture was extracted with ethyl acetate. The organicphase was washed by brine, dried over sodium sulfate, and evaporated.The residue was purified by silica-gel column chromatography (petroleumether-ethyl acetate) to afford compound 11 (12.5 g, yield: 32%).

LC/MS (method 6) RT=1.30, [M+H]⁺=338

Step 2

To a solution of compound 11 (3.5 g, 10.4 mmol) and 2-(2,6-difluorophenyl)acetic acid (1.97 g, 11.4 mmol) in Py(40 mL) was addedEDCI (3.96 g, 20.8 mmol), and the mixture was stirred at roomtemperature overnight. The reaction mixture was evaporated, and theresidue was purified by silica-gel column chromatography(dichloromethane-ethyl acetate) to afford compound I-65 (3.10 g, yield:61%).

¹H-NMR (DMSO-d₆): 2.42 (3H, s), 2.60 (3H, s), 3.91 (2H, s), 7.10-7.15(2H, t, J=7.8 Hz), 7.39-7.45 (1H, m), 12.87 (1H, s).

Example 8 Synthesis of Compound I-61

A mixture of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3-thiazole (51.5 mg,0.244 mmol), compound I-65 (30 mg, 0.061 mmol), Pd₂(dba)₃ (5.60 mg,0.006 mmol), tricyclohexylphosphine (2.60 mg, 0.009 mmol) and cesiumcarbonate (43.8 mg, 0.134 mmol) in 1,4-dioxane (1 mL) was stirred at120° C. under microwave for 30 minutes. To the reaction mixture wasadded sodium hydrogen carbonate aqueous solution, and the mixture wasextracted with chloroform-methanol (9:1). The organic phase wasevaporated, and the residue was added DMSO. The precipitate wasfiltered, and the resulting filtrate was purified by reverse-phasepreparative HPLC (10 mM ammonium carbonate aqueoussolution-acetonitrile) to afford compound I-61 (17.9 mg, yield: 65%).

¹H-NMR (DMSO-d₆) δ: 2.66 (3H, s), 3.92 (2H, s), 7.09-7.18 (2H, m), 7.24(1H, d, J=1.8 Hz), 7.38-7.47 (1H, m), 9.15 (1H, d, J=1.8 Hz), 12.72 (1H,brs).

Example 9 Synthesis of Compound I-92

Step 1

Under nitrogen atmosphere, to a solution of compound 12 (3.50 g, 16.0mmol) in THF (27 mL) were added isobutyl chloroformate (2.32 mL, 17.6mmol) and Et₃N (2.45 mL, 17.6 mmol) under ice-cooling, and the mixturewas stirred at the same temperature for 30 minutes. The precipitate inthe reaction mixture was filtered, and the resulting solid was washed byTHF. To a solution of sodium borohydride (1.82 g, 48.1 mmol) in water(20 mL)-THF (20 mL) was added the resulting filtrate at 0° C., and themixture was stirred at the same temperature for 30 minutes. To thereaction mixture was added 2 mol/L hydrochloric acid, and the mixturewas extracted with ethyl acetate. The organic phase was washed bysaturated sodium hydrogen carbonate aqueous solution and brine, driedover anhydrous magnesium sulfate, and evaporated. The residue wassolidified by hexane-ethyl acetate and filtered to afford compound 13(2.75 g, yield: 84%).

¹H-NMR (CDCl₃) δ: 3.06 (3H, s), 4.85 (2H, s), 7.59 (1H, d, J=9.1 Hz),7.71 (2H, s).

Step 2

Under nitrogen atmosphere, to a solution of compound 13 (2.70 g, 13.2mmol) in dichloromethane (27 mL) were added Et₃N (2.20 mL, 15.9 mmol)and MsCl (1.24 mL, 15.9 mmol) at 0° C., and the mixture was stirred for28 hours with heating to room temperature. To the reaction mixture wasadded water, and the mixture was extracted with ethyl acetate. Theorganic phase was washed by saturated sodium hydrogen carbonate aqueoussolution, water and brine, dried over anhydrous magnesium sulfate, andevaporated. The residue was purified by silica-gel column chromatography(hexane-ethyl acetate). The resulting solid was suspended in hexane andfiltered to afford compound 14 (2.27 g, yield: 77%).

¹H-NMR (CDCl₃) δ: 3.08 (3H, s), 4.68 (2H, s), 7.69 (2H, t, J=8.1 Hz),7.76 (1H, d, J=7.8 Hz).

Step 3

To a solution of compound 14 (1.70 g, 7.63 mmol) in DMF (17 mL) wasadded sodium cyanide (561 mg, 0.202 mmol), and the mixture was stirredat room temperature for 15.5 hours. To the reaction mixture was addedsodium iodide (114 mg, 0.763 mmol), and the mixture was stirred at roomtemperature for 2.5 hours. To the reaction mixture was added sodiumhydrogen carbonate aqueous solution, and the mixture was extracted withethyl acetate. The organic phase was washed by water and brine, driedover anhydrous magnesium sulfate, and evaporated. The residue waspurified by silica-gel column chromatography (hexane-ethyl acetate). Theresulting solid was suspended in hexane and filtered to afford compound15 (256.1 mg, yield: 16%).

¹H-NMR (CDCl₃) δ: 3.08 (3H, s), 3.87 (2H, s), 7.67-7.76 (2H, m),7.77-7.85 (1H, m).

Step 4

To a suspension of compound 15 (150 mg, 0.670 mmol) in methanol (4.5 mL)was added acetyl chloride (0.753 mL, 10.6 mmol), and the mixture wasstirred at room temperature for 42 hours. To the reaction mixture wasadded saturated sodium hydrogen carbonate aqueous solution, and themixture was extracted with ethyl acetate. The organic phase was washedby brine, dried over anhydrous magnesium sulfate, and evaporated, toafford compound 16 (168.3 mg, yield: 97%).

¹H-NMR (CDCl₃) δ: 3.07 (3H, s), 3.74 (3H, s), 3.77 (2H, s), 7.50 (1H, t,J=7.4 Hz), 7.63-7.74 (2H, m).

Step 5

To a solution of compound 16 (165 mg, 0.670 mmol) in THF (3 mL) wasadded 2 mol/L sodium hydroxide aqueous solution (0.402 mL, 0.804 mmol),and the mixture was stirred at room temperature for 2 hours. To thereaction mixture was added 2 mol/L hydrochloric acid, and the mixturewas extracted with ethyl acetate. The organic phase was washed by brine,dried over anhydrous magnesium sulfate, and evaporated. The resultingsolid was suspended in hexane and filtered to afford compound 17 (139.3mg, yield: 90%).

¹H-NMR (CDCl₃+DMSO-d₆) δ: 3.09 (3H, s), 3.74 (2H, s), 7.55 (1H, t, J=7.5Hz), 7.64 (1H, d, J=8.6 Hz), 7.70 (1H, d, J=8.1 Hz).

Step 6

To a solution of compound 17 (39 mg, 0.168 mmol) in DMF (1 mL) wereadded Py (0.016 mL, 0.202 mmol), HATU (77 mg, 0.202 mmol) and compound 3(39 mg, 0.185 mmol), and the mixture was stirred at room temperature for14 hours. Py (0.016 mL, 0.202 mmol) and HATU (77 mg, 0.202 mmol) wereadded to the reaction mixture, and the mixture was stirred at roomtemperature for 22 hours. To the reaction mixture was added sodiumhydrogen carbonate aqueous solution, the precipitate was filtered, andthe resulting solid was washed by water and dichloromethane. Thefiltrate was evaporated, and then the residue was purified by silica-gelcolumn chromatography (hexane-ethyl acetate). The resulting solid wassuspended in hexane-ethyl acetate and then filtered to afford I-92 (10.1mg, yield: 14%).

¹H-NMR (CDCl₃) δ: 2.57 (311H, s), 2.67 (311H, s), 3.08 (311H, s), 3.91(2H, s), 6.93 (1H, s), 7.59 (1H, t, J=7.4 Hz), 7.68-7.81 (2H, m), 9.11(1H, s).

Example 10 Synthesis of Compound I-93

Step 1

To a mixture of potassium thiocyanate (5.67 g, 58.0 mmol) and acetone(45 mL) was added compound 18 (7.77 g, 58.0 mmol), and the mixture wasstirred at room temperature overnight. The reaction mixture wasevaporated, and then the residue was dissolved in ethanol (30 mL). Tothe resulting mixture was added concentrated hydrochloric acid (15 mL),and the mixture was heated overnight at reflux. The precipitate wasfiltered, and the resulting solid was washed by water and dried toafford compound 19 (4.30 g, yield: 47%).

Step 2

To a solution of compound 19 (0.500 g, 3.16 mmol) in acetic acid (5 mL)was added bromine (0.51 g, 3.16 mmol) under ice-cooling, and the mixturewas stirred at room temperature overnight. The reaction mixture waspoured into water and extracted with ethyl acetate. The organic phasewas washed by brine, dried over sodium sulfate, and evaporated, toafford crude product (0.500 g) of compound 20.

Step 3

To a solution of crude product (0.500 g) of compound 20 in ethanol (10mL) was added thiourea (0.160 g, 2.10 mmol), and the mixture was stirredat room temperature overnight. The reaction mixture was evaporated,water was added to the resulting solid and filtered, and the filteredsolid was dried, to afford compound 21 (0.400 g, yield: 89%).

Step 4

To a solution of compound 21 (390 mg, 1.83 mmol) and2-(2,6-difluorophenyl)acetic acid (315 mg, 1.83 mmol) in Py (15 mL) wasadded EDCI (703 mg, 3.66 mmol), and the mixture was stirred at 60° C.overnight. The reaction mixture was poured into water and extracted withethyl acetate. The organic phase was washed by brine, dried over sodiumsulfate, and evaporated. The residue was purified by preparative TLC(petroleum ether-ethyl acetate) to afford compound I-93 (35.0 mg, yield:5.20%).

¹H-NMR (DMSO-d₆): 2.29 (3H, s), 3.91 (2H, s), 7.08 (1H, s), 7.11-7.16(2H, m), 7.40-7.46 (1H, m), 11.31 (1H, s), 12.66 (1H, s).

Example 11 Synthesis of Compound I-117

Step 1

To a solution of compound 22 (5.00 g, 25.1 mmol) in ethanol (15 mL) wasadded 28% (w/w) ammonia aqueous solution (3.39 mL, 50.1 mmol), themixture was stirred at 70° C. for 3 hours. The reaction mixture wascooled to room temperature, and then to the mixture was added sodiumhydrogen carbonate aqueous solution. The precipitate was filtered, andthe resulting solid was washed by water and then dried, to affordcompound 23 (3.08 g, yield: 68%).

¹H-NMR (DMSO-d₆) δ: 8.38 (2H, s).

Step 2

To a solution of compound 23 (12.0 g, 66.7 mmol) in THF (240 mL) wereadded N,N-dimethyl-4-aminopyridine (0.407 g, 3.33 mmol), di-tert-butyldicarbonate (18.6 mL, 80.0 mmol), and the mixture was stirred at 50° C.for 1 hour. The reaction mixture was evaporated, and to the residue wasadded dichloromethane-methanol. The insoluble matter in the solution wasfiltered, the filtrate was evaporated, and the residue was purified bysilica-gel column chromatography (hexane-ethyl acetate). Methanol-waterwas added to the resulting oil, the mixture was solidified, and theprecipitate was filtered, to afford compound 24 (15.8 g, yield: 84%).

¹H-NMR (CDCl₃) δ: 1.62 (9H, s), 9.10 (1H, s).

Step 3

To a mixture of compound 24 (3.1 g, 11.1 mmol),2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)thiazole(3.97 g, 16.6 mmol), cesium fluoride (3.36 g, 22.1 mmol) and Pd catalyst27 (0.392 g, 0.553 mmol) were added 1,4-dioxane (30 mL) and water (3mL), and the mixture was stirred at 80° C. for 3 hours under nitrogenatmosphere. The reaction mixture was cooled to room temperature, then tothe mixture was added water, and the mixture was extracted with ethylacetate. The organic phase was washed by brine, dried over anhydrousmagnesium sulfate, and evaporated. The residue was purified bysilica-gel column chromatography (hexane-ethyl acetate) to afford crudeproduct (3.85 g) of compound 25.

¹H-NMR (CDCl₃) δ: 1.54 (9H, s), 2.68 (3H, s), 2.77 (3H, s), 8.84 (1H,brs).

Step 4

To crude product (3.85 g) of compound 25 was added TFA (15.0 mL, 195mmol), and the reaction mixture was stirred at room temperature for 2hours. The reaction mixture was evaporated, then 2 mol/L sodiumhydroxide aqueous solution was added to the residue, and the reactionmixture was adjusted to basic. To the resulting mixture was addeddiethyl ether, and the precipitate was filtered. The resulting solid waswashed by ether and water and dried to afford compound 26 (1.78 g,yield: 76%, 2 steps).

¹H-NMR (DMSO-d₆) δ: 2.59 (3H, s), 2.65 (3H, s), 8.08 (2H, s).

Step 5

Under nitrogen atmosphere, to a solution of2-(4-(trifluoromethylsulfonyl)phenyl)acetic acid (1.06 g, 3.96 mmol) inTHF (10 mL) were added oxalyl chloride (0.375 mL, 4.29 mmol) and DMF(0.026 mL, 0.330 mmol), and the mixture was stirred at room temperaturefor 15 minutes (defined as “the reaction mixture A” in the followings).Under nitrogen atmosphere, to a solution of compound 26 (700 mg, 3.30mmol) in THF (14 mL) was added Py (0.800 mL, 9.89 mmol) at roomtemperature and then added the reaction mixture A under ice-cooling, andthe mixture was stirred at the same temperature for 30 minutes. Afterstirred at room temperature for 1.5 hours, the reaction mixture wasevaporated. To the residue were added2-(4-(trifluoromethylsulfonyl)phenyl)acetic acid (1.06 g, 3.96 mmol),HATU (1.50 g, 3.96 mmol), and Py (0.64 mL, 7.91 mmol), and the mixturewas stirred at 80° C. for 2 hours. To the reaction mixture was addedsodium hydrogen carbonate aqueous solution, and the mixture wasextracted with ethyl acetate. The organic phase was washed by water andbrine, dried over anhydrous magnesium sulfate, and evaporated. Theresidue was purified by silica-gel column chromatography (hexane-ethylacetate). The resulting solid was suspended in diisopropyl ether andthen filtered (defined as “solid 1” in the followings). The filtrate wasconcentrated, and then the residue was purified by silica-gel columnchromatography (hexane-ethyl acetate). The resulting solid was suspendedin diisopropyl ether and then filtered (defined as “solid 2” in thefollowings). The solid 1 and the solid 2 were dissolved in methanol-THF,and evaporated. To the resulting oil was added diisopropyl ether, themixture was solidified, and then the precipitate was filtered, to affordcompound I-117 (1.20 g, yield: 78%).

¹H-NMR (DMSO-d₆) δ: 2.64 (3H, s), 2.72 (3H, s), 4.18 (2H, s), 7.81 (2H,d, J=7.9 Hz), 8.13 (2H, d, J=8.1 Hz), 13.45 (1H, s).

Example 12 Synthesis of Compound I-131

Step 1

To a solution of compound 18 (10 g, 74.3 mmol) in acetic acid (10 mL)was added ethyl thiooxamate (9.9 g, 74.3 mmol), and the mixture wasstirred at 80° C. for 2 hours 30 minutes. The reaction mixture wasevaporated, to the residue was added ethyl acetate, and the solution waswashed by saturated sodium hydrogen carbonate aqueous solution and brineand dried over sodium sulfate. The mixture was evaporated to affordcrude product (11.3 g, yield: 71%) of compound 28.

¹H-NMR (CDCl₃) δ: 1.48 (t, J=7.1 Hz, 3H), 2.63 (s, 3H), 2.83 (s, 3H),4.53 (q, J=7.1 Hz, 2H).

Step 2

To a solution of crude product (11.3 g, 53.0 mmol) of compound 28 inchloroform (70 mL) was added pyridinium tribromide (18.6 g, 58.3 mmol)under ice-cooling, the mixture was stirred at room temperature for 5hours. The reaction mixture was evaporated, to the residue was addedmethanol (70 mL), and the residue was dissolved. To the resultingmixture was added thiourea (6.1 g, 79 mmol), and the mixture was stirredat room temperature for 2 hours. The reaction mixture was evaporated,and to the residue was added ethyl acetate. The solution was washed bysaturated sodium hydrogen carbonate aqueous solution and brine, driedover sodium sulfate, and evaporated, to afford crude product (12.8 g,yield: 90%) of compound 29.

¹H-NMR (DMSO-d₆) δ: 1.31 (t, J=7.1 Hz, 3H), 2.58 (s, 3H), 4.33 (q, J=7.1Hz, 2H), 6.98 (s, 1H), 7.32 (s, 1H).

Step 3

Under nitrogen atmosphere, to a solution of2-(4-chloro-1H-pyrazole-1-yl)acetic acid (1.94 g, 12.1 mmol) in THF (15mL) were added oxalyl chloride (1.06 mL, 12.1 mmol), and DMF (20 μL),and the mixture was stirred at room temperature for 1 hour. Theresulting solution was added dropwise to a mixture of crude product (3.1g, 11.5 mmol) of compound 28 and Py (2.8 mL, 34.5 mmol) in DMF (15 mL).After stirred at room temperature for 1 hour, to saturated sodiumhydrogen carbonate aqueous solution (160 mL) was added the reactionmixture. The resulting solid was filtered, and the resulting solid waswashed by water and hexane and dried, to afford crude product (3.63 g,yield: 76%) of compound 30.

¹H-NMR (DMSO-d₆) δ: 1.33 (t, J=7.1 Hz, 3H), 2.64 (s, 3H), 4.36 (q, J=7.1Hz, 2H), 5.17 (s, 2H), 7.59 (s, 1H), 7.64 (s, 1H), 8.01 (s, 1H), 12.80(s, 1H).

Step 4

To a solution of crude product (2 g, 4.86 mmol) of compound 30 in2-propanol (25 mL) was added sodium borohydride (367 mg, 9.71 mmol) atroom temperature. The reaction mixture was stirred at 50° C. for 7 hoursand cooled in an ice water bath, then to the mixture was added 2 mol/Lhydrochloric acid aqueous solution (6 mL), and the mixture was stirredfor 10 minutes. To the resulting solution was added ethyl acetate, andthe organic phase was washed by saturated sodium hydrogen carbonateaqueous solution and brine, and dried over sodium sulfate. Afterevaporated, the residue was purified by silica gel chromatography(chloroform-methanol) to afford compound I-131 (850 mg, yield: 47%).

¹H-NMR (DMSO-d₆) δ: 2.53 (s, 311H), 4.67 (d, J=5.7 Hz, 2H), 5.16 (s,2H), 6.02 (t, J=5.7 Hz, 1H), 7.35 (s, 1H), 7.58 (s, 1H), 8.02 (s, 1H),12.71 (brs, 1H).

Example 13 Synthesis of Compound I-127

To compound 30 (0.940 g, 2.28 mmol) was added 2 mol/L ammonia methanolsolution (40.0 mL, 80.0 mmol), and the mixture was stirred at roomtemperature for 14 hours. To the reaction mixture was added 2 mol/Lhydrochloric acid (80 mL), the precipitate was filtered, and theresulting solid was washed by water. The resulting solid was suspendedin dichloromethane-THF and then filtered. The resulting solid wassuspended in methanol and filtered to afford I-127 (434 mg, yield: 50%).

¹H-NMR (DMSO-d₆) δ: 2.63 (311H, s), 5.17 (2H, s), 7.56 (1H, s), 7.59(1H, s), 7.80 (1H, s), 8.02 (1H, s), 8.09 (1H, s), 12.80 (1H, s).

Example 14 Synthesis of Compound I-145

Step 1

To a mixture of compound 31 (70 mg, 0.268 mmol),orthochlorophenylboronic acid (46 mg, 0.295 mmol) and Pd catalyst 34(8.5 mg, 0.013 mmol) were added THF (700 μL) and 2 mol/L potassiumcarbonate aqueous solution (402 μL), and the mixture was stirred withheating at 110° C. under microwave for 30 minutes under nitrogenatmosphere. To the reaction mixture was added ethyl acetate, the organicphase was washed by saturated sodium hydrogen carbonate aqueous solutionand brine, and evaporated. The residue was purified by silica gel pad(chloroform-methanol) to afford crude product of compound 32.

LC/MS (method 5) RT=2.29, [M+H]⁺=293.2

Step 2

To a solution of crude product of compound 32 in dichloromethane (400μL) was added TFA (300 μL), and the mixture was stirred at roomtemperature for 16 hours. The reaction mixture was evaporated, toluenewas added to the mixture, and the mixture was evaporated, to affordcrude product of compound 33.

LC/MS (method 5) RT=1.48, [M+H]⁺=237.1

Step 3

A solution of crude product of compound 33, compound 3 (54 mg, 0.255mmol) and EDC (51 mg, 0.268 mmol) in DMF (600 μL) was stirred at roomtemperature for 6 hours. To the mixture was added compound 3 (51 mg,0.268 mmol), and the mixture was stirred at room temperature for 12hours. To the reaction mixture was added ethyl acetate, the organicphase was washed by saturated sodium hydrogen carbonate aqueous solutionand brine, dried over sodium sulfate, and evaporated, and then theresidue was purified by silica-gel column chromatography(chloroform-methanol), to afford compound I-145 (37 mg, yield: 32%).

¹H-NMR (DMSO-d₆) δ: 2.58 (s, 3H), 5.21 (s, 2H), 7.26 (t, J=7.3 Hz, 1H),7.29 (s, 1H), 7.35 (t, J=7.1 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.61 (d,J=7.5 Hz, 1H), 7.90 (s, 1H), 8.27 (s, 1H).

Example 15 Synthesis of Compound I-156

Step 1

To a solution of 2-(4-(chlorosulfonyl)phenyl)acetic acid (2.50 g, 10.7mmol) in dichloromethane (30 mL) were added oxalyl chloride (0.994 mL,11.4 mmol) and DMF (0.055 mL, 0.710 mmol), and the mixture was stirredat room temperature for 10 minutes. To the reaction mixture was addedoxalyl chloride (0.497 mL, 5.68 mmol), and the mixture was stirred atroom temperature for 10 minutes. After the reaction solvent wasevaporated, the residue was dissolved in THF (30 mL). Under nitrogenatmosphere, to the resulting mixture was added THF (45 mL) solution ofcompound 3 (1.5 g, 7.10 mmol) and Et₃N (2.95 mL, 21.3 mmol) underice-cooling, and the mixture was stirred at the same temperature for 10minutes. To the reaction mixture were added water and saturated sodiumhydrogen carbonate aqueous solution under ice-cooling, and the mixturewas extracted with ethyl acetate. The organic phase was washed by brine,dried over anhydrous magnesium sulfate, and evaporated. The residue waspurified by silica-gel column chromatography (chloroform-ethyl acetate)to afford compound 35 (1.20 g, yield: 40%).

¹H-NMR (CDCl₃) δ: 2.56 (3H, s), 2.66 (3H, s), 3.83 (2H, s), 6.95 (1H,s), 7.49-7.55 (2H, m), 7.97-8.07 (2H, m), 9.68 (1H, s).

Step 2

To a solution of compound 35 (100 mg, 0.234 mmol) and Et₃N (0.039 mL,0.280 mmol) in dichloromethane (2 mL) was added piperidine (0.028 mL,3.33 mmol), and the mixture was stirred at room temperature for 10minutes. To the reaction mixture was added saturated sodium hydrogencarbonate aqueous solution, the mixture was stirred, and the organicphase was purified by silica-gel column chromatography (hexane-ethylacetate), to afford I-156 (80.3 mg, yield: 72%).

¹H-NMR (DMSO-d₆) δ: 1.28-1.42 (2H, m), 1.47-1.61 (4H, m), 2.59 (3H, s),2.80-2.94 (4H, m), 3.93 (2H, s), 7.29 (1H, s), 7.58 (2H, d, J=8.2 Hz),7.70 (2H, d, J=8.2 Hz), 12.64 (1H, s).

Example 16 Synthesis of Compound I-191

Step 1

To a solution of compound 3 (500 mg, 2.36 mmol) in DMF (3 mL) were addedDIEA (620 μL, 3.55 mmol) and chloroacetyl chloride (206 μL, 2.60 mmol)at room temperature, and the mixture was stirred at room temperature for1 hour. To the reaction mixture was added chloroacetyl chloride (40 μL,0.50 mmol), and the mixture was stirred for 1 hour. To the resultingmixture was added sodium azide (231 mg, 3.55 mmol), and the mixture wasstirred at room temperature for 2 hours. To the reaction mixture wasadded ethyl acetate, and the mixture was washed by saturated sodiumhydrogen carbonate aqueous solution and brine, and dried over sodiumsulfate. After evaporated, the residue was purified by silica-gel columnchromatography (hexane-ethyl acetate) to afford compound 36 (317 mg,yield: 45%).

¹H-NMR (CDCl₃) δ: 2.59 (s, 3H), 2.68 (s, 3H), 4.28 (s, 2H), 6.96 (s,1H), 9.65 (brs, 1H).

Step 2

To a solution of compound 36 (30 mg, 0.102 mmol) and ethynylbenzene(11.5 mg, 0.112 mmol) in DMF (150 μL) were added sodium ascorbate (4 mg,0.02 mmol) and copper(I) iodide (1.9 mg, 0.01 mmol), and the mixture wasstirred at room temperature for 90 minutes under nitrogen atmosphere. Tothe reaction mixture was added chloroform-methanol, and the mixture waswashed by brine and dried over sodium sulfate. After evaporated, theresidue was purified by silica-gel column chromatography(chloroform-methanol) and solidified by ethyl acetate-hexane to affordcompound I-191 (29 mg, yield: 72%).

¹H-NMR (DMSO-d₆) δ: 2.61 (s, 3H), 5.55 (s, 2H), 7.33-7.38 (m, 2H), 7.47(t, J=7.6 Hz, 2H), 7.88 (d, J=7.8 Hz, 2H), 8.63 (s, 1H), 12.95 (s, 1H).

Example 17 Synthesis of Compound I-210

Step 1

To a mixture of compound 3 (300 mg, 1.42 mmol), compound 37 (414 mg,1.42 mmol) and HATU (648 mg, 1.70 mmol) were added DMF (0.4 mL) and Py(2 mL), and the mixture was stirred at 60° C. for 4 hours. The reactionmixture was extracted with ethyl acetate, the organic phase was washedby 10% citric acid aqueous solution, saturated sodium hydrogen carbonateaqueous solution and brine, dried over sodium sulfate, and evaporated.The residue was purified by silica-gel column chromatography(hexane-ethyl acetate) to afford compound I-210 (320 mg, yield: 46%).

¹H-NMR (DMSO-d₆) δ: 1.22-1.44 (m, 9H), 2.21-2.34 (m, 1H), 2.37-2.47 (m,1H), 2.60 (s, 311H), 3.26-3.32 (m, 1H), 3.49-3.59 (m, 1H), 3.84-3.96 (m,1H), 4.60 (dd, J=18.3, 7.9 Hz, 1H), 7.21-7.28 (m, 1H), 7.29-7.37 (m,5H), 12.52-12.58 (m, 1H).

Example 18 Synthesis of Compound I-178

Compound I-210 (300 mg, 0.62 mmol) was dissolved in dichloromethane (1mL) and TFA (1 mL), and stirred at room temperature for 1 hour. Thereaction mixture was evaporated, ethyl acetate was added to the mixture,and the mixture was washed by saturated sodium hydrogen carbonateaqueous solution and brine, dried over sodium sulfate, and evaporated toafford compound I-178 (234 mg, yield: 98%).

¹H-NMR (DMSO-d₆) δ: 2.12-2.22 (m, 1H), 2.27-2.34 (m, 1H), 2.60 (s,311H), 2.86 (t, J=9.4 Hz, 1H), 3.18-3.28 (m, 1H), 3.40 (dd, J=9.6, 7.2Hz, 1H), 4.09 (dd, J=9.3, 3.8 Hz, 1H), 7.18-7.24 (m, 1H), 7.27-7.34 (m,5H).

Example 19 Synthesis of Compound I-218

To a solution of compound I-178 (117 mg, 0.30 mmol) in THF (1 mL) wereadded DIEA (59 μL, 0.33 mmol) and trifluoroacetic anhydride (47 μL, 0.33mmol), and the mixture was stirred at room temperature for 40 minutes.To the reaction mixture was added ethyl acetate, and the mixture waswashed by saturated sodium hydrogen carbonate aqueous solution and brineand dried over sodium sulfate. After evaporated, the residue waspurified by silica-gel column chromatography (hexane-ethyl acetate) toafford compound I-218 (143 mg, yield: 98%).

¹H-NMR (CDCl₃) δ: 2.26-2.35 (m, 1H), 2.57 (s, 3H), 2.67 (s, 3H), 2.76(dd, J=12.9, 6.3 Hz, 1H), 3.73 (t, J=10.5 Hz, 1H), 3.86-3.96 (m, 1H),4.29 (t, J=9.1 Hz, 1H), 5.02 (d, J=8.2 Hz, 1H), 6.94 (s, 1H), 7.24-7.42(m, 5H), 10.14 (s, 1H).

Example 20 Synthesis of Compound II-1

To a solution of compound 3 (100 mg, 0.473 mmol) in Py (2 mL) was addedphenylmethanesulfonyl chloride (135 mg, 0.710 mmol), and the mixture wasstirred at room temperature for 18 hours. To the reaction mixture wasadded sodium hydrogen carbonate aqueous solution, and the mixture wasextracted with ethyl acetate. The organic phase was washed by water andbrine, dried over anhydrous magnesium sulfate, and evaporated. Theresidue was purified by silica-gel column chromatography (hexane-ethylacetate) and then purified by preparative TLC (ethyl acetate) to affordcompound II-1 (6.3 mg, yield: 4%).

¹H-NMR (CDCl₃) δ: 2.41 (3H, s), 2.62 (3H, s), 4.30 (2H, s), 6.30 (1H,s), 7.15-7.36 (5H, m).

Example 21 Synthesis of Compound II-2

Step 1

To a solution of compound 1 (purity: 97%) (4.00 g, 25.0 mmol) inchloroform (40 mL) was added pyridinium bromide perbromide (purity: 90%)(10.7 g, 30.0 mmol), and the mixture was heated at reflux for 2.5 hours.To the reaction mixture was added pyridinium bromideperbromide (purity:90%) (4.44 g, 12.5 mmol), and the mixture was heated at reflux for 1hour. The reaction mixture was evaporated, and then about half of theresidue was dissolved in ethanol (30 mL). To the resulting mixture wasadded ethyl thiooxamate (2 g, 12.5 mmol), and the mixture was stirred at60° C. for 2.5 hours. The reaction mixture was cooled to roomtemperature, then to the mixture was added saturated sodium hydrogencarbonate aqueous solution, and the mixture was extracted with ethylacetate. The organic phase was washed by water and brine, dried overanhydrous magnesium sulfate, and evaporated. The residue was purified bysilica gel pad (THF) and then silica-gel column chromatography(hexane-ethyl acetate). The resulting solid was suspended in diisopropylether and filtered to afford compound 38 (849 mg, yield: 13%).

¹H-NMR (DMSO-d₆) δ: 1.35 (3H, t, J=7.1 Hz), 2.54 (3H, s), 2.63 (3H, s),4.40 (2H, q, J=7.1 Hz), 8.17 (1H, s).

Step 2

To a solution of compound 38 (733 mg, 2.73 mmol) in THF (7.5 mL) wasadded 2 mol/L sodium hydroxide aqueous solution (2.049 mL, 4.10 mmol),and the mixture was stirred at room temperature for 2 hours. Thereaction mixture was diluted with water, then to the mixture was added 2mol/L hydrochloric acid, and the mixture was adjusted to pH3-4. Theprecipitate was filtered, and the resulting solid was washed by waterand then dried, to afford compound 39 (390 mg, yield: 59%).

¹H-NMR (DMSO-d₆) δ: 2.53 (3H, s), 2.61 (3H, s), 8.10 (1H, s).

Step 3

To a suspension of compound 39 (50.0 mg, 0.208 mmol) in DMA (1 mL) wereadded Et₃N (0.035 mL, 0.250 mmol), HATU (95.0 mg, 0.250 mmol) and(3-fluorophenyl)methaneamine (0.029 mL, 0.250 mmol), and the mixture wasstirred at room temperature for 2 hours. To the reaction mixture wasadded saturated sodium hydrogen carbonate aqueous solution, and themixture was extracted with ethyl acetate. The organic phase wasevaporated, and the residue was purified by silica-gel columnchromatography (hexane-ethyl acetate). The residue was solidified byhexane-ethyl acetate and filtered to afford compound II-2 (37.9 mg,yield: 52%).

¹H-NMR (CDCl₃) δ: 2.59 (3H, s), 2.68 (3H, s), 4.67 (2H, d, J=6.2 Hz),6.95-7.04 (1H, m), 7.05-7.11 (1H, m), 7.12-7.18 (1H, m), 7.33 (1H, td,J=8.0, 5.9 Hz), 7.50 (1H, s), 7.52-7.64 (1H, m).

Example 22 Synthesis of Compound II-4

Step 1

To a solution of compound 1 (1 g, 6.44 mmol) in chloroform (10 mL) wasadded pyridinium tribromide (2.27 g, 7.09 mmol), and the mixture wasstirred at 60° C. for 4 hours. To the reaction mixture was addedpyridinium tribromide (700 mg, 2.18 mmol), and the mixture was stirredat 60° C. for 1 hour. The reaction mixture was evaporated, to themixture were added methanol (10 mL) and compound 40 (1.04 g, 7.09 mmol),and the mixture was stirred at room temperature for 14 hours. To theresulting mixture was added ethyl acetate, and the mixture was washed bysaturated sodium hydrogen carbonate aqueous solution and brine and driedover sodium sulfate. After evaporated, the residue was purified bysilica gel chromatography (hexane-ethyl acetate) to afford compound 41(958 mg, yield: 51%).

¹H-NMR (DMSO-d₆) δ: 2.60 (s, 3H), 3.69 (s, 3H), 4.24 (s, 2H), 7.74 (s,1H).

Step 2

To a solution of compound 41 (250 mg, 0.932 mmol) in 2-propanol (1.5 mL)was added sodium borohydride (70 mg, 1.86 mmol), and the mixture wasstirred at 60° C. for 3 hours. To the reaction mixture was added 2 mol/Lhydrochloric acid aqueous solution, and the mixture was stirred for 1hours. The resulting mixture was extracted with ethyl acetate, and theorganic phase was washed by saturated sodium hydrogen carbonate aqueoussolution and brine and dried over sodium sulfate. The mixture wasevaporated to afford crude product (183 mg, yield: 81%) of compound 42.

¹H-NMR (DMSO-d₆) δ: 2.59 (s, 3H), 3.12 (t, J=6.2 Hz, 2H), 3.75 (dd,J=11.5, 6.2 Hz, 2H), 4.96 (t, J=5.2 Hz, 1H), 7.62 (s, 1H).

Step 3

To a solution of crude product (100 mg, 0.416 mmol) of compound 42,triphenylphosphine (109 mg, 0.416 mmol), and 4-bromophenol (79 mg, 0.458mmol) in THF (700 μL) was added diisopropyl azodicarboxylate (89 μL,0.458 mmol), and the mixture was stirred at room temperature for 20hours. To the reaction mixture was added ethyl acetate, and the mixturewas washed by saturated sodium hydrogen carbonate aqueous solution andbrine and dried over sodium sulfate. After evaporated, the residue waspurified by silica-gel column chromatography (hexane-ethyl acetate) andpreparative TLC (hexane-ethyl acetate) to afford compound II-4 (30 mg,yield: 18%).

¹H-NMR (CDCl₃) δ: 2.58 (s, 3H), 2.68 (s, 3H), 3.50 (t, J=6.3 Hz, 2H),4.34 (t, J=6.3 Hz, 2H), 6.80-6.85 (m, 2H), 7.16 (s, 1H), 7.36-7.41 (m,2H).

Example 23 Synthesis of Compound II-25

To a solution of compound 2 (0.15 g, 0.64 mmol) in ethanol (3.0 mL) wasadded 1-(4-acetylphenyl)thiourea (0.12 g, 0.64 mmol), and the mixturewas heated at reflux for 3 hours. The reaction mixture was cooled andthen evaporated. To the residue were added potassium carbonate aqueoussolution and ethyl acetate, and the mixture was extracted with ethylacetate. The organic phase was washed by water, dried over anhydrousmagnesium sulfate, and evaporated. The residue was purified bysilica-gel column chromatography (hexane-ethyl acetate) to affordcompound II-25 (0.061 g, yield: 29%).

¹H-NMR (DMSO-d₆) δ: 2.53 (s, 3H), 2.54 (s, 3H), 2.61 (s, 3H), 7.09 (s,1H), 7.77 (d, J=8.88 Hz, 2H), 7.96 (d, J=8.88 Hz, 2H), 10.8 (s, 1H).

Example 24 Synthesis of Compound I-444

Step 1

A solution of compound 58 (10 g, 45 mmol), N,O-dimethylhydroxylaminehydrochloride (5.3 g, 54 mmol) and EDCI (17.3 g, 90 mmol) in DMF (20 mL)was stirred at room temperature overnight. To the reaction mixture wasadded saturated sodium hydrogen carbonate aqueous solution, and themixture was extracted with ethyl acetate. The organic phase was washedby brine, dried over anhydrous magnesium sulfate, and evaporated. Theresidue was purified by silica-gel column chromatography(chloroform-ethyl acetate) to afford compound 59 (7.5 g, yield: 63%).

¹H-NMR (DMSO-D₆) δ: 2.62 (d, J=6.0 Hz, 3H), 3.26 (s, 3H), 3.72 (s, 3H).

Step 2

To a solution of compound 59 (7.5 g, 28 mmol) in THF (20 mL) was added 3mol/L methyl magnesium bromide ether solution at 0° C., and the mixturewas stirred at room temperature for 1 hour. To the reaction mixture wasadded water, the mixture was filtered, and the resulting filtrate wasextracted with ethyl acetate. The organic phase was dried over anhydrousmagnesium sulfate and evaporated. The residue was purified by silica-gelcolumn chromatography (chloroform-ethyl acetate) to afford compound 60(5.1 g, yield: 82%).

¹H-NMR (DMSO-D₆) δ: 2.54 (d, J=3.6 Hz, 3H), 2.64 (d, J=6.1 Hz, 3H).

Step 3

A solution of compound 60 (5.1 g, 23 mmol) and pyridinium tribromide(9.7 g, 30 mmol) in chloroform (50 mL) was stirred at reflux for 1 hour.The reaction mixture was evaporated to afford crude product of compound61.

Step 4

A solution of crude product of compound 61 and thiourea (1.9 g, 25 mmol)in ethanol (50 mL) was stirred at reflux for 1 hour. The reactionmixture was evaporated, and to the residue was added 2 mol/L sodiumhydroxide aqueous solution. The precipitate was filtered and washed bywater and hexane to afford compound 62 (5.7 g, 2 Step yield: 89%).

¹H-NMR (DMSO-D₆) δ: 2.49 (s, 3H), 6.81 (s, 1H), 7.31 (br s, 2H).

Step 5

A suspension of compound 62 (100 mg, 0.36 mmol) and excess potassiumcarbonate in methanol (2 mL) was stirred at 50° C. for 2 hours. Thereaction mixture was stirred at reflux for 5 hours. The reaction mixturewas evaporated, and the residue was purified by silica-gel columnchromatography (chloroform-methanol) to afford compound 63 (50 mg,yield: 61%).

LC/MS (method 5) RT=0.97, [M+H]⁺=228.

Step 6

A solution of compound 63 (50 mg, 0.22 mmol),2-(4-(trifluoromethylsulfonyl)phenyl)acetic acid (88 mg, 0.33 mmol), andEDCI (84 mg, 0.44 mmol) in DMF (2 mL) was stirred at room temperaturefor 2 hours. Saturated sodium hydrogen carbonate aqueous solution wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic phase was washed by brine and dried over anhydrousmagnesium sulfate, and evaporated. The residue was purified bypreparative LC/MS (formic acid containing acetonitrile-formic acidcontaining water) to afford compound I-444 (71 mg, yield: 68%).

¹H-NMR (DMSO-D₆) δ: 2.41 (s, 3H), 4.01 (s, 3H), 4.04 (s, 2H), 7.22 (s,1H), 7.80 (d, J=8.0 Hz, 2H), 8.12 (d, J=8.0 Hz, 2H), 12.68 (br s, 1H).

Example 25 Synthesis of Compound I-395

Step 1

To a solution of compound 48 (830 mg, 1.43 mmol) in dichloromethane(16.6 mL) was added thionyl chloride (0.206 mL, 2.85 mmol) underice-cooling, and the mixture was stirred at 0° C. for 3.5 hours. To thereaction mixture was added saturated sodium hydrogen carbonate aqueoussolution, and the mixture was neutralized and extracted withdichloromethane. The organic phase was washed by water, dried overanhydrous magnesium sulfate, and evaporated. To a solution of theresidue (813 mg, 1.35 mmol) in DMF (16 mL) were added water (1.6 mL) andsodium cyanide (110 mg, 2.26 mmol), and the mixture was stirred at roomtemperature for 5.5 hours. To the reaction mixture was added water, andthe mixture was extracted with ethyl acetate. The organic phase waswashed by water and brine, dried over anhydrous magnesium sulfate, andevaporated. The residue was purified by silica-gel column chromatography(hexane-ethyl acetate) to afford compound 64 (418 mg, 3 steps yield:40%).

¹H-NMR (CDCl₃) δ: 1.10 (9H, s), 1.57 (9H, s), 4.20 (2H, s), 4.93 (2H,s), 7.01 (1H, s), 7.39-7.52 (6H, m), 7.69 (4H, d, J=7.5 Hz), 8.00 (1H,s).

Step 2

To a solution of compound 64 (418 mg, 0.707 mmol) in dichloromethane (4mL) was added TFA (2 mL), and the mixture was stirred at roomtemperature for 0.5 hours. To the reaction mixture was added saturatedsodium hydrogen carbonate aqueous solution, and the mixture wasneutralized and extracted with dichloromethane. The organic phase waswashed by water, dried over anhydrous sodium sulfate, and evaporated.The residue was purified by silica-gel column chromatography(hexane-ethyl acetate) to afford compound 65 (240 mg, yield: 69%).

¹H-NMR (CDCl₃) δ: 1.15 (9H, s), 4.22 (2H, s), 4.92 (2H, s), 5.02 (2H,s), 6.65 (1H, s), 7.40-7.46 (6H, m), 7.69 (4H, d, J=7.5 Hz).

Step 3

To a solution of compound 65 (136 mg, 0.277 mmol) in Py (1.4 mL) wereadded compound 57 (82 mg, 0.333 mmol) and{{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethlene}dimethylammoniumhexafluorophosphate (356 mg, 0.852 mmol). The mixture was stirred at 80°C. for 3 hours. To the reaction mixture was added saturated sodiumhydrogen carbonate aqueous solution, and the mixture was extracted withethyl acetate. The organic phase was washed by water and brine, driedover anhydrous magnesium sulfate, and evaporated. The residue waspurified by silica-gel column chromatography (hexane-ethyl acetate) toafford compound 66 (76 mg, yield: 38%).

¹H-NMR (CDCl₃) δ: 1.14 (9H, s), 3.69-3.76 (1H, m), 4.27 (2H, s),4.43-4.53 (4H, m), 4.92 (2H, s), 7.10 (1H, s), 7.40-7.46 (6H, m), 7.69(4H, d, J=12.1 Hz), 8.50 (2H, s), 9.73 (1H, br s).

Step 4

To a solution of compound 66 (76 mg, 0.106 mmol) in THF (1 mL) was added1.0 mmol/L tetrabutylammonium fluoride (0.128 mL, 0.128 mmol). Themixture was stirred at room temperature for 45 minutes. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic phase was washed by water and brine, dried overanhydrous magnesium sulfate, and evaporated. The residue was purified bysilica-gel column chromatography (hexane-ethyl acetate). The resultingoil was solidified by diethyl ether and then filtered to afford compoundI-395 (20 mg, yield: 39%).

¹H-NMR (DMSO-D₆) δ: 3.83-3.91 (1H, m), 4.26-4.28 (2H, m), 4.36 (2H, t,J=8.9 Hz), 4.43 (2H, s), 4.73 (2H, d, J=5.8 Hz), 6.20 (1H, t, J=5.8 Hz),7.48 (1H, s), 8.72 (2H, s), 12.55 (1H, s).

Example 26 Synthesis of Compound II-31

Under nitrogen atmosphere, to a solution of compound 3 (100 mg, 0.473mmol) in NMP (1 mL) was added sodium hydride (20.8 mg, 0.521 mmol,purity: 60%). The mixture was stirred at room temperature for 15minutes. To the reaction mixture was added2-(4-chlorophenyl)acetonitrile (216 mg, 1.42 mmol), and the mixture wasstirred at room temperature for 30 minutes. The mixture was then stirredat 120° C. for 12 hours. After cooled, to the reaction mixture wereadded water and saturated sodium hydrogen carbonate aqueous solution,and then the mixture was extracted with ethyl acetate. The organic phasewas washed by water and brine, dried over anhydrous magnesium sulfate,and evaporated. The residue was purified by silica-gel columnchromatography (hexane-ethyl acetate). To the residue were added ethylacetate and 2 mol/L hydrochloric acid. After the aqueous phase wasseparated, then saturated sodium hydrogen carbonate aqueous solution wasadded to the aqueous phase, and the mixture was extracted with ethylacetate. The organic phase was washed by brine, dried over anhydrousmagnesium sulfate, and evaporated. The residue was purified bypreparative TLC (hexane-ethyl acetate) to afford compound II-31 (3.8 mg,yield: 2.2%).

¹H-NMR (DMSO-D₆) δ: 2.47 (3H, s), 2.58 (3H, s), 3.59 (2H, s), 7.20 (1H,s), 7.39 (4H, s), 8.67 (1H, br s), 9.23 (1H, br s).

Example 27 Synthesis of Compound II-49

Step 1

To a suspension of compound 67 (500 mg, 2.72 mmol) in THF (5 mL) wereadded benzoyl isothiocyanate (0.439 mL, 3.27 mmol) and Et₃N (1.132 mL,8.17 mmol), and the mixture was stirred at room temperature for 2 hours.To the reaction mixture were added methanol (2.5 mL) and 2 mol/L sodiumhydroxide aqueous solution (2.72 mL, 5.44 mmol), and the mixture washeated at reflux for 1 hour. To the reaction mixture was added brine,and the mixture was extracted with ethyl acetate. The organic phase waswashed by brine, dried over anhydrous sodium sulfate, and evaporated.The residue was solidified by diethyl ether and then filtered to affordcompound 68 (440 mg, yield: 78%).

¹H-NMR (DMSO-d₆) δ: 2.54-2.72 (m, 3H), 2.96 (dd, J=14.6, 6.7 Hz, 2H),3.34-3.46 (m, 2H), 6.82-7.05 (br, 1H), 7.08-7.13 (m, 2H), 7.17-7.22 (m,2H), 7.69-7.91 (br, 1H).

Step 2

To a suspension of compound 68 (106 mg, 0.513 mmol) in ethanol (0.9 mL)was added a solution of compound 3 (2.14 ml, 0.427 mmol) in ethanol (0.2mL), and the mixture was heated at reflux for 2 hours. To the reactionmixture was added 5% sodium hydrogen carbonate aqueous solution-brine(1:1), and the mixture was extracted with ethyl acetate. The organicphase was washed by brine, dried over anhydrous sodium sulfate, andevaporated. The residue was purified by silica-gel column chromatography(hexane-ethyl acetate) to afford compound II-49 (123 mg, yield: 85%).

¹H-NMR (DMSO-d₆) δ: 2.46 (s, 3H), 2.55 (s, 3H), 2.65-2.80 (m, 3H), 3.02(dd, J=15.3, 7.0 Hz, 2H), 3.22-3.29 (t, J=6.0 Hz, 2H), 6.68 (s, 1H),7.09-7.14 (m, 2H), 7.19-7.23 (m, 2H), 7.92-7.98 (m, 1H).

The following compounds were synthesized in a manner similar to thosedescribed in the general procedures for the synthesis of the compound ofthe invention and Examples. The chemical structure of the compounds andthe physical properties (LC/MS data and NMR spectra) of them aredescribed below. “Wedged bond” and “dashed bond” in the chemical formularepresent configuration. In particular, in the compounds whereinconfiguration is described, the compounds wherein “racemic” is describedin the item of chirality are racemic compounds that are specified inrelative configuration, and the compounds wherein “chiral” is describedin the item of chirality as configuration are compounds that haveabsolute configuration.

(Method of Identification for the Compound)

LC/MS data of a compound of the present invention were measured underany one of the following 10 conditions (Methods 1 to 10), and aretention time and [M+H]⁺ were shown.

(Method 1) Column: Shim-pack XR-ODS (2.2 μm, i.d. 50×3.0 mm) (Shimadzu)

Flow rate: 1.6 mL/minUV detection wavelength: 254 nmMobile phase: [A] is 0.1% formic acid containing aqueous solution, and[B] is 0.1% formic acid containing acetonitrile solutionGradient: Linear gradient of 10% to 100% solvent [B] for 3 minutes wasperformed, and 100% solvent [B] was maintained for 0.5 minute.

(Method 2) Column: Xbridge C18 (5 μm, i.d. 4.6×50 mm) (Waters)

Flow rate: 3 mL/minUV detection wavelength: 254 nmMobile phase: [A] is 0.1% formic acid containing aqueous solution, and[B] is 0.1% formic acid containing acetonitrile solutionGradient: Linear gradient of 10% to 100% solvent [B] for 3 minutes wasperformed, and 100% solvent [B] was maintained for 1 minute.

(Method 3) Column: Gemini-NX (5 μm, i.d. 4.6×50 mm) (Phenomenex)

Flow rate: 3 mL/minUV detection wavelength: 254 nmMobile phase: [A] is 0.1% formic acid containing aqueous solution, and[B] is 0.1% formic acid containing methanol solutionGradient: Linear gradient of 5% to 100% solvent [B] for 3.5 minutes wasperformed, and 100% solvent [B] was maintained for 0.5 minute.

(Method 4) Column: ACQUITY UPLC(R)BEH C18 (1.7 μm, i.d. 2.1×50 mm)(Waters)

Flow rate: 1.0 mL/minUV detection wavelength: 254 nmMobile phase: [A] is 0.1% formic acid containing aqueous solution, and[B] is 0.1% formic acid containing acetonitrile solutionGradient: Linear gradient of 5% to 100% solvent [B] for 3.5 minutes wasperformed, and 100% solvent [B] was maintained for 0.5 minute.

(Method 5) Column: ACQUITY UPLC(R)BEH C18 (1.7 μm, i.d. 2.1×50 mm)(Waters)

Flow rate: 0.8 mL/minUV detection wavelength: 254 nmMobile phase: [A] is 0.1% formic acid containing aqueous solution, and[B] is 0.1% formic acid containing acetonitrile solutionGradient: Linear gradient of 5% to 100% solvent [B] for 3.5 minutes wasperformed, and 100% solvent [B] was maintained for 0.5 minute.

(Method 6) Column: Xbridge C18 (3.5 μm, i.d. 4.6×50 mm)

Flow rate: 2.0 mL/minUV detection wavelength: 254 nmMobile phase: [A] is 0.05% trifluoroacetic acid containing aqueoussolution, and [B] is 0.05% trifluoroacetic acid containing acetonitrilesolution Gradient: Linear gradient of 5% to 100% solvent [B] for 5minutes was performed, and 100% solvent [B] was maintained for 0.9minute.

(Method 7) Column: Shim-pack XR-ODS (2.2 μm, i.d. 50×3.0 mm) (Shimadzu)

Flow rate: 1.6 mL/minUV detection wavelength: 254 nmMobile phase: [A] is 0.1% formic acid containing aqueous solution, and[B] is 0.1% formic acid containing acetonitrile solutionGradient: Linear gradient of 10% to 100% solvent [B] for 8 minutes wasperformed, and 100% solvent [B] was maintained for 0.5 minute.

(Method 8) Column: ACQUITY UPLC(R)BEH C18 (1.7 μm, i.d. 2.1×50 mm)(Waters)

Flow rate: 0.55 mL/minUV detection wavelength: 254 nmMobile phase: [A] is 0.1% formic acid containing aqueous solution, and[B] is 0.1% formic acid containing acetonitrile solutionGradient: Linear gradient of 5% to 100% solvent [B] for 3 minutes wasperformed, and 100% solvent [B] was maintained for 0.5 minute.

(Method 9) Column: Xbridge C18 (3.5 μm, i.d. 4.6×50 mm)

Flow rate: 2.0 mL/minUV detection wavelength: 254 nmMobile phase: [A] is 0.05% trifluoroacetic acid containing aqueoussolution, and [B] is 0.05% trifluoroacetic acid containing acetonitrilesolutionGradient: Linear gradient of 5% to 100% solvent [B] for 1.6 minutes wasperformed, and 100% solvent [B] was maintained for 1.4 minutes.

(Method 10) Column: Xbridge C18 (3.5 μm, i.d. 4.6×50 mm)

Flow rate: 2.0 mL/minUV detection wavelength: 254 nmMobile phase: [A] is 0.05% trifluoroacetic acid containing aqueoussolution, and [B] is 0.05% trifluoroacetic acid containing acetonitrilesolution.Gradient: Linear gradient of 5% to 100% solvent [B] for 5 minutes wasperformed, and 100% solvent [B] was maintained for 1 minute.

TABLE 1 LC/MS No. Chamical Structure Chirality [M + H] RT method I-1

358 2.38 1 I-2

390 2.55 1 I-3

392 2.55 1 I-4

378 2.42 1 I-5

360 2.15 1 I-6

310 1.66 1 I-7

331 1.25 1 I-8

348 2.08 1 I-9

310 2.17 1

TABLE 2 I-10

368 2.40 1 I-11

408 2.62 1 I-12

394 2.46 1 I-13

394 2.24 1 I-14

394 2.26 1 I-15

438 2.70 1 I-16

414 2.52 1 I-17

408 1.34 2 I-18

344 1.87 1 I-19

398 3.23 3

TABLE 3 I-20

416 3.23 3 I-21

414 3.21 3 I-22

430 3.31 3 I-23

280 1.58 1 I-24

448 2.29 1 I-25

474 2.45 1 I-26

296 1.34 1 I-27

316 1.67 1 I-28

294 1.78 1 I-29

498 2.40 1

TABLE 4 I-30

328 1.80 1 I-31

480 2.27 1 I-32

282 1.65 1 I-33

294 1.68 1 I-34

330 1.79 1 I-35

476 2.05 1 I-36

444 1.85 1 I-37

racemic 322 1.38 1 I-38

336 1.82 1 I-39

racemic 405 1.15 1

TABLE 5 I-40

279 1.08 4 I-41

408 1.48 4 I-42

chiral 323 0.89 4 I-43

356 1.96 4 I-44

369 1.65 4 I-45

322 1.46 4 I-46

385 2.06 4 I-47

413 1.52 4 I-48

382 1.98 4 I-49

382 1.96 4

TABLE 6 I-50

354 1.47 4 I-51

372 1.10 4 I-52

366 1.84 4 I-53

380 1.77 4 I-54

308 1.71 4 I-55

racemic 342 2.00 1 I-56

racemic 333 1.64 1 I-57

racemic 454 1.80 1 I-58

350 1.92 1 I-59

423 2.13 1

TABLE 7 I-60

443 1.38 5 I-61

449 1.89 5 I-62

446 1.71 5 I-63

443 1.65 5 I-64

458 1.94 5 I-65

492 2.22 1 I-66

476 2.40 5

TABLE 8 I-67

485 2.26 5 I-68

485 2.22 5 I-69

458 1.89 5 I-70

458 1.94 5 I-71

406 2.20 5 I-72

380 1.91 5 I-73

468 2.47 5

TABLE 9 I-74

396 1.50 1 I-75

485 2.11 1 I-76

382 1.68 1 I-77

373 1.92 1 I-78

373 1.91 1 I-79

408 1.59 1 I-80

422 1.69 1 I-81

409 1.16 1 I-82

519 2.24 5

TABLE 10 I-83

499 1.93 5 I-84

510 1.98 5 I-85

519 2.23 5 I-86

519 2.30 5 I-87

493 2.22 5 I-88

357 1.92 1 I-89

391 1.99 1 I-90

313 1.37 1

TABLE 11 I-91

381 1.94 1 I-92

426 1.64 1 I-93

368 1.73 1 I-94

424 2.23 1 I-95

360 1.62 1 I-96

382 1.75 1 I-97

410 1.91 1 I-98

394 2.21 1 I-99

360 1.81 5

TABLE 12 I-100

414 2.17 5 I-101

387 1.11 5 I-102

380 2.00 5 I-103

382 1.57 5 I-104

399 1.91 1 I-105

439 1.91 5 I-106

345 1.60 1 I-107

411 1.70 1 I-108

420 2.06 1 I-109

316 1.89 5

TABLE 13 I-110

390 1.95 5 I-111

436 2.39 5 I-112

352 1.98 5 I-113

409 1.95 1 I-114

423 2.10 1 I-115

473 1.97 1 I-116

355 1.70 5 I-117

463 2.21 5 I-118

400 192 5

TABLE 14 I-119

409 1.57 5 I-120

317 1.71 5 I-121

355 1.68 5 I-122

436 1.69 5 I-123

345 1.36 5 I-124

388 1.79 5 I-125

439 1.73 5 I-126

466 1.49 5 I-127

383 1.57 5

TABLE 15 I-128

410 2.10 1 I-129

394 2.17 1 I-130

396 1.85 1 I-131

370 1.45 5 I-132

398 1.64 5 I-133

412 1.55 5 I-134

396 1.89 5 I-135

440 1.65 5 I-136

404 1.67 5

TABLE 16 I-137

398 2.16 5 I-138

339 1.68 5 I-139

382 2.11 5 I-140

338 1.58 5 I-141

476 1.81 5 I-142

478 1.94 5 I-143

458 1.68 5 I-144

414 1.37 5 I-145

430 2.03 5

TABLE 17 I-146

430 2.08 5 I-147

430 2.09 5 I-148

397 0.96 5 I-149

439 1.37 5 I-150

474 1.52 5 I-151

474 1.50 5 I-152

413 1.36 5 I-153

429 1.15 5

TABLE 18 I-154

399 1.22 5 I-155

399 1.28 5 I-156

477 2.07 1 I-157

479 1.75 1 I-158

529 2.12 1 I-159

499 2.14 1 I-160

533 2.31 1 I-161

533 2.30 1 I-162

533 2.20 1 I-163

524 2.06 1

TABLE 19 I-164

485 1.95 1 I-165

500 1.68 1 I-166

474 1.61 1 I-167

398 1.23 1 I-168

397 0.85 1 I-169

439 1.41 1 I-170

415 1.68 1 I-171

429 1.12 1 I-173

332 1.42 1

TABLE 20 I-174

494 1.75 1 I-175

371 2.10 1 I-176

453 2.11 1 I-177

357 1.89 1 I-178

chiral 385 1.16 1 I-179

chiral 385 1.15 1 I-180

358 1.99 1 I-181

423 2.05 1

TABLE 21 I-182

439 1.65 1 I-183

chiral 413 1.26 1 I-184

chiral 413 1.25 1 I-185

401 1.96 1 I-186

462 2.15 1 I-187

345 1.05 1 I-188

466 1.21 1 I-189

419 1.46 1

TABLE 22 I-190

403 1.90 1 I-191

3.97 1.74 1 I-192

chiral 385 1.15 1 I-193

chiral 385 1.15 1 I-194

463 2.03 1 I-195

426 2.33 1 I-196

533 2.13 1 I-197

481 1.97 1

TABLE 23 I-198

409 1.23 1 I-199

415 1.51 1 I-200

445 1.49 1 I-201

471 2.37 1 I-202

chiral 328 1.44 1 I-203

chiral 328 1.41 1 I-204

435 2.18 1 I-205

365 1.88 1 I-206

385 1.93 1

TABLE 24 I-207

401 1.68 1 I-208

469 1.13 1 I-209

415 0.96 1 I-210

chiral 485 2.43 1 I-211

chiral 485 2.46 1 I-212

chiral 485 2.46 1 I-213

407 1.40 1 I-214

457 1.82 1 I-215

chiral 385 1.17 1 I-216

chiral 385 1.17 1

TABLE 25 I-217

chiral 399 1.18 1 I-218

chiral 481 2.27 1

TABLE 26 No. Chamical Structure Chirality NMR I-219

¹H-NMR (DMSO-d₆) δ: 0.90 (t, J = 7.35 Hz 3H), 1.62 (td, J = 7.10, 14.7Hz, 2H), 2.42 (t, J = 7.10 Hz, 2H), 2.51 (s, 3H), 2.59 (s, 3H), 7.26 (s,1H), 12.3 (s, 1H). I-220

¹H-NMR (DMSO-d₆) δ: 0.84 (t, J = 6.84 Hz, 3H), 1.15-1.35 (m, 16H), 1.59(m, 2H), 2.43 (t, J = 7.35 Hz, 2H), 2.50 (s, 3H), 2.59 (s, 3H), 7.25 (s,1H), 12.7 (s, 1H). I-221

¹H-NMR (DMSO-d₆) δ: 0.86 (t, J = 6.84 Hz, 3H), 1.15-1.35 (m, 8H), 1.59(m, 2H), 2.43 (t, J = 7.35 Hz, 2H), 2.50 (s, 3H), 2.59 (s, 3H), 7.25 (s,1H), 12.7 (s, 1H). I-222

¹H-NMR (DMSO-d₆) δ: 0.87 (t, J = 6.84 Hz, 3H), 1.20-1.35 (m, 4H), 1.64(m, 2H), 2.43 (t, J = 7.35 Hz, 2H), 2.50 (s, 3H), 2.59 (s, 3H), 7.25 (s,1H), 12.3 (s, 1H). I-223

¹H-NMR (DMSO-d₆) δ: 1.15-1.90 (m, 11H), 2.50 (s, 3H), 2.59 (s, 3H), 7.25(s, 1H), 12.2 (s, 1H). I-224

¹H-NMR (DMSO-d₆) δ: 1.50-1.95 (m, 8H), 2.51 (s, 3H), 2.59 (s, 3H), 2.94(m, 1H), 7.25 (s, 1H), 12.3 (s, 1H).

TABLE 27 I-225

¹H-NMR (DMSO-d₆) δ: 2.50 (s, 3H), 2.60 (s, 3H), 3.78 (s, 2H), 7.28 (s,1H), 7.29 (d, J = 8.00 Hz, 2H), 7.53 (d, J = 8.00 Hz, 2H), 12.6 (s, 1H).I-226

¹H-NMR (DMSO-d₆) δ: 1.70-2.30 (m, 6H), 2.50 (s, 3H), 2.59 (s, 3H), 3.38(m, 1H), 7.26 (s, 1H), 12.2 (s, 1H). I-227

¹H-NMR (DMSO-d₆) δ: 2.54 (s, 3H), 2.61 (s, 3H), 7.37 (s, 1H), 7.63 (d, J= 8.62 Hz, 2H), 8.13 (d, J = 8.62 Hz, 2H), 12.9 (s, 1H). I-228

¹H-NMR (DMSO-d₆) δ: 2.50 (s, 3H), 2.59 (s, 3H), 2.77 (t, J = 7.60 Hz,2H), 2.93 (t, J = 7.60 Hz, 2H), 7.10-7.35 (m, 6H), 12.3 (s, 1H). I-229

¹H-NMR (DMSO-d₆) δ: 2.51 (s, 3H), 2.60 (s, 3H), 4.89 (s, 2H), 7.00 (m,2H), 7.32 (s, 1H), 7.36 (m, 2H), 12.6 (s, 1H). I-230

¹H-NMR (DMSO-d₆) δ: 2.50 (s, 3H), 2.60 (s, 3H), 3.80 (s, 2H), 7.28 (s,1H), 7.30 (d, J = 8.62 Hz, 2H), 7.54 (d, J = 8.62 Hz, 2H), 12.8 (s, 1H).I-231

1H-NMR (CDCl3) δ: 9.40 (1H, s), 7.50 (2H, d, J = 7.6 Hz), 7.16 (2H, d, J= 7.6 Hz), 6.99 (1H, s), 3.75 (3H, s), 2.45 (3H, s), 2.36 (3H, s). I-232

¹H-NMR (DMSO-d₆) δ: 2.53 (s, 3H), 2.61 (s, 3H), 7.37 (s, 1H), 7.77 (d, J= 8.62 Hz, 2H), 8.05 (d, J = 8.62 Hz, 2H), 12.9 (s, 1H). I-233

¹H-NMR (DMSO-d₆) δ: 2.51 (s, 3H), 2.59 (s, 3H), 7.20 (s, 1H), 7.40-7.55(m, 4H), 8.96 (s, 1H), 10.9 (s, 1H). I-234

¹H-NMR (DMSO-d₆) δ: 2.54 (s, 3H), 2.61 (s, 3H), 7.36 (s, 1H), 7.55 (t, J= 7.86 Hz, 2H), 7.65 (t, J = 7.35 Hz, 1H), 8.12 (d, J = 7.60 Hz, 2H),12.8 (s, 1H).

TABLE 28 LC/MS No. Chamical Structure Chirality [M + H] RT method I-235

racemic 508 1.89 1 I-236

549 1.53 1 I-237

521 1.39 1 I-238

racemic 410 1.90 1 I-239

racemic 386 1.98 1 I-240

417 0.89 1 I-241

387 0.91 1 I-242

chiral 501 2.34 1

TABLE 29 I-243

chiral 485 2.35 1 I-244

chiral 401 1.09 1 I-245

chiral 485 2.44 1 I-246

chiral 485 2.35 1 I-247

417 1.01 1 I-248

344 1.25 1 I-249

chiral 409 1.91 1 I-250

chiral 497 2.21 1 I-251

chiral 443 1.79 1

TABLE 30 I-252

chiral 459 1.65 1 I-253

422 1.76 1 I-254

422 1.76 1 I-255

507 1.80 1 I-256

399 1.59 1 I-257

467 1.93 1 I-258

453 1.27 1 I-259

440 1.98 1 I-260

453 1.23 1

TABLE 31 I-261

457 1.64 1 I-262

453 1.25 1 I-263

443 1.07 1 I-264

503 2.11 1 I-265

chiral 459 2.24 1 I-266

chiral 473 2.36 1 I-267

324 1.17 1 I-268

324 1.54 1 I-269

324 1.47 1 I-270

486 2.55 1

TABLE 32 I-271

chiral 481 2.25 1 I-272

chiral 568 1.44 1 I-273

444 2.09 1 I-274

chiral 468 1.07 1 I-275

chiral 492 1.20 1 I-276

chiral 564 1.42 1 I-277

501 2.18 1 I-278

441 1.94 1

TABLE 33 I-279

409 1.00 1 I-280

439 2.37 1 I-281

377 1.54 1 I-282

454 1.10 1 I-283

415 1.08 1 I-284

441 1.74 1 I-285

449 1.39 1 I-286

440 2.01 1 I-287

racemic 492 2.04 1 I-288

chiral 443 2.06 1

TABLE 34 I-289

chiral 427 1.88 1 I-290

chiral 497 2.07 1 I-291

chiral 455 2.18 1 I-292

chiral 467 2.48 1 I-293

chiral 535 2.48 1 I-294

chiral 440 1.26 1 I-295

415 2.09 1 I-296

393 2.49 1 I-297

456 1.71 1

TABLE 35 I-298

racemic 342 1.52 1 I-299

racemic 342 1.49 1 I-300

chiral 456 1.96 1 I-301

chiral 491 2.14 1 I-302

471 2.01 8 I-303

472 1.70 8 I-304

421 1.57 1 I-305

519 1.87 8 I-306

519 1.95 8

TABLE 36 I-307

457 1.81 8 I-308

437 1.69 8 I-309

456 1.86 8 I-310

456 1.76 8 I-311

466 1.76 8 I-312

chiral 471 1.98 1 I-313

chiral 473 1.99 1 I-314

chiral 527 2.11 1 I-315

chiral 487 2.02 1

TABLE 37 I-316

549 2.35 1 I-317

499 1.29 1 I-318

497 1.14 1 I-319

483 1.37 1 I-320

520 1.78 1 I-321

483 1.42 1 I-322

498 1.26 8 I-323

chiral 459 1.80 1 I-324

498 1.31 8

TABLE 38 I-325

498 1.34 8 I-326

328 1.84 1 I-327

471 2.01 8 I-328

chiral 489 1.92 1 I-329

465 1.92 8 I-330

486 2.15 5 I-331

450 2.11 1 I-332

466 1.96 1 I-333

380 1.72 1

TABLE 39 I-334

480 2.09 1 I-335

484 2.22 5 I-336

chiral 543 1.85 1 I-337

chiral 499 2.00 1 I-338

chiral 549 2.08 1 I-339

396 1.57 1 I-340

470 1.83 8 I-341

445 2.08 5 I-342

437 1.77 5

TABLE 40 I-343

437 1.83 5 I-344

chiral 503 1.83 1 I-345

513 1.93 8 I-346

484 2.17 1 I-347

500 2.02 1 I-348

499 1.94 1 I-349

505 1.84 1 I-350

556 2.28 8

TABLE 41 I-351

513 1.94 1 I-352

568 1.46 1 I-353

512 1.89 1 I-354

468 2.36 8 I-355

360 1.57 5 I-356

408 1.75 5 I-357

408 1.77 5 I-358

521 1.65 1 I-359

503 1.89 1

TABLE 42 I-360

522 1.76 1 I-361

415 1.12 1 I-362

diasteromer of I-361 415 1.12 1 I-363

605 1.78 1 I-364

589 1.93 5 I-365

454 2.52 5 I-366

508 1.73 1 I-367

481 1.48 5

TABLE 43 I-368

481 1.52 5 I-369

455 2.21 5 I-370

551 1.81 1 I-371

403 1.64 5 I-372

421 1.67 5 I-373

537 1.82 5 I-374

468 2.13 5 I-375

577 1.42 1

TABLE 44 I-376

591 1.74  1 I-377

591 1.33  1 I-378

521 1.92  1 I-379

469 2.27  1 I-380

462 3.24 10 I-381

536 1.74  5 I-382

535 1.75  5 I-383

551 1.76  5

TABLE 45 I-384

572 1.86  5 I-385

563 1.60  5 I-386

457 2.05  1 I-387

racemic 476 3.30 10 I-388

chiral 455 2.04  1 I-389

550 1.78  5 I-390

564 1.84  5 I-391

550 1.78  5

TABLE 46 I-392

487 2.23 5 I-393

549 1.86 5 I-394

chiral 455 2.04 1 I-395

482 1.70 1 I-396

477 1.62 5 I-397

519 1.93 5 I-398

520 1.84 5 I-399

555 2.06 5 I-400

535 2.09 5

TABLE 47 I-401

455 1.98 1 I-402

473 2.33 8 I-403

443 1.79 5 I-404

490 1.61 5 I-405

454 2.17 1 I-406

404 1.46 1 I-407

535 1.75 1 I-408

408 2.06 1 I-409

345 1.10 1 I-410

416 1.58 1

TABLE 48 I-411

505 1.85 5 I-412

521 1.53 5 I-413

449 1.82 1 I-414

387 1.42 1 I-415

415 1.69 1 I-416

455 2.00 1 I-417

441 1.82 1 I-418

485 1.81 1 I-419

388 2.77 10 I-420

racemic 402 2.87 10

TABLE 49 I-421

450 1.57 5 I-422

475 1.47 5 I-423

431 2.00 5 I-424

427 1.80 5 I-425

426 1.59 5 I-426

398 1.29 5 I-427

440 1.45 5 I-428

400 1.58 5 I-429

388 1.28 5

TABLE 50 I-430

361 1.43 5 I-431

365 1.34 5 I-432

463 1.79 1 I-433

471 1.65 5 I-434

565 2.02 5 I-435

551 1.94 5 I-436

565 1.81 5 I-437

492 1.96 5

TABLE 51 I-438

579 1.96 5 I-439

629 2.19 5 I-440

594 1.75 5 I-441

504 1.61 5 I-442

395 1.71 1 I-443

456 2.14 1 I-444

478 2.38 5 I-445

522 2.38 5

TABLE 52 I-446

598 2.78 5 I-447

415 1.62 1 I-448

I-449

499 2.13 5 I-450

350 1.91 1 I-451

464 2.03 5 I-452

513 1.78 5 I-453

485 1.96 5 I-454

chiral 492 1.95 1 I-455

chiral 492 1.96 1

TABLE 53 I-456

478 1.91 1 I-457

364 2.04 1 I-458

394 1.90 1 I-459

492 2.25 5 I-460

560 2.50 5 I-461

508 2.08 5 I-462

358 1.78 1 I-463

561 1.88 5 I-464

489 1.82 1

TABLE 54 I-465

diastereomer of I-464 489 1.80 1 I-466

392 1.98 1 I-467

racemic 469 2.16 1 I-468

521 1.88 1 I-469

449 1.89 5 I-470

370 1.94 1 I-471

519 1.89 1 I-472

racemic 549 1.90 5 I-473

racemic 470 1.84 1

TABLE 55 I-474

racemic 551 1.92 5 I-475

519 1.82 1 I-476

511 2.07 1 I-477

445 1.34 1 I-478

chiral (Chirality is not determined) 551 1.93 5 I-479

chiral (Chirality is not determined) enantiomer of I-478 551 1.93 5I-480

254 1.18 1 I-481

chiral (Chirality is not determined) 549 1.83 5 I-482

chiral (Chirality is not determined) enantiomer of I-481 549 1.83 5

TABLE 56 I-483

563 1.78 1 I-484

496 2.24 1 I-485

540 1.99 1 I-486

594 2.48 5 I-487

546 1.80 1 I-488

388 1.80 1 I-489

531 2.08 1 I-490

531 2.08 1

TABLE 57 I-491

465 1.28 1 I-492

453 2.35 1 I-493

454 1.85 1 I-494

chiral 469 1.87 1 I-495

523 2.08 1 I-496

453 2.41 1 I-497

439 2.27 1 I-498

553 2.09 1 I-499

567 2.04 1 I-500

racemic 508 1.77 1

TABLE 58 I-501

503 1.84 1 I-502

491 1.75 1 I-503

503 2.11 1 I-504

561 2.13 1 I-505

468 1.96 1 I-506

532 2.06 1 I-507

512 2.11 1 I-508

518 2.25 1 I-509

389 1.52 1 I-510

609 2.33 1

TABLE 59 I-511

547 1.89 1 I-512

racemic 481 2.55 1 I-513

605 2.11 1 I-514

618 1.40 1 I-515

591 1.87 1 I-516

556 2.11 1 I-517

576 2.19 1 I-518

546 1.86 1

TABLE 60 I-519

racemic 553 2.66 1 I-520

599 1.91 1 I-521

629 2.31 1 I-522

601 2.35 1 I-523

chiral 625 2.42 5 I-524

chiral 639 2.26 5 I-525

547 2.24 1 I-526

531 2.12 1

TABLE 61 I-527

racemic 527 2.07 1 I-528

513 1.98 1 I-529

racemic 497 2.14 1 I-530

racemic 559 2.75 1 I-531

racemic 483 2.44 1 I-532

racemic 469 2.15 1 I-533

racemic 457 2.34 1 I-534

441 1.88 1 I-535

384 2.48 1 I-536

racemic 422 2.25 1

TABLE 62 I-537

446 2.50 5 I-538

448 2.24 5 I-539

424 2.11 1 I-540

352 1.89 1 I-541

375 1.70 5 I-542

409 1.58 5 I-543

426 2.48 5 I-544

429 1.92 1 I-545

392 2.19 1

TABLE 63 No. Chamical Structure Chirality NMR I-546

1H-NMR (DMSO-D₆) δ: 12.35 (1.0H, s), 7.49-7.47 (1.0H, m), 7.36-7.19(5.0H, m), 6.09 (1.0H, t, J = 5.9 Hz), 5.36 (1.0H, t, J = 5.6 Hz), 4.71(2.0H, d, J = 5.9 Hz), 4.64 (2.0H, d, J = 5.6 Hz), 3.54- 3.45 (1.0H, m),2.67-2.50 (3.0H, m), 2.39-2.33 (2.0H, m). I-547

1H-NMR (CDCl₃) δ: 9.54 (1.0H, s), 7.35-7.19 (5.0H, m), 6.96 (1.0H, s),4.91 (2.0H, d, J = 5.4 Hz), 3.45- 3.38 (1.0H, m), 3.20-3.09 (1.0H, m),2.65-2.42 (7.0H, m). I-548

1H-NMR (CDCl₃) δ: 11.01 (1.0H, s), 7.38-7.29 (5.0H, m), 6.99 (1.0H, s),4.90 (2.0H, s), 4.82 (2.0H, d, J = 5.6 Hz), 4.46 (2.0H, s), 4.36-4.30(1.0H, m), 3.24-3.17 (2.0H, m), 2.63-2.55 (2.0H, m), 2.36-2.25 (2.0H,m). I-549

1H-NMR (CDCl₃) δ: 7.40-7.27 (5.0H, m), 6.95 (1.0H, s), 4.83 (2.0H, s),4.79 (2.0H, s), 4.46 (2.0H, s), 4.06-3.99 (1.0H, m), 3.49 (1.0H, s),2.82-2.73 (1.0H, m), 2.52-2.48 (2.0H, m), 2.38-2.35 (2.0H, m). I-550

1H-NMR (CDCl₃) δ: 9.90 (1.0H, s), 7.61 (2.0H, d, J = 7.8 Hz), 7.47(2.0H, d, J = 8.0 Hz), 7.02 (1.0H, s), 4.88-4.85 (4.0H, m), 4.52 (2.0H,s), 4.14-4.02 (1.0H, m), 2.85-2.74 (1.0H, m), 2.64-2.54 (2.0H, m),2.54-2.48 (1.0H, m), 2.47-2.35 (2.0H, m). I-551

1H-NMR (CDCl₃) δ: 9.90 (1.0H, s), 7.61 (2.0H, d, J = 7.8 Hz), 7.47(2.0H, d, J = 8.0 Hz), 7.02 (1.0H, s), 4.88-4.85 (4.0H, m), 4.52 (2.0H,s), 4.14-4.02 (1.0H, m), 2.85-2.74 (1.0H, m), 2.64-2.54 (2.0H, m),2.54-2.48 (1.0H, m), 2.47-2.35 (2.0H, m). I-552

1H-NMR (CDCl₃) δ: 9.54 (1.0H, s), 6.98 (1.0H, s), 5.87 (1.0H, td, J =56.9, 2.9 Hz), 4.91 (2.0H, br s), 3.23-3.15 (2.0H, m), 2.89-2.74 (1.0H,m), 2.59 (3.0H, s), 2.58-2.49 (2.0H, m), 2.38-2.29 (2.0H, m).

TABLE 64 LC/MS No. Chamical Structure Chirality [M + H] RT method II-1

366 1.57 1 II-2

348 2.05 1 II-3

368 1.95 1 II-4

395 2.52 1 II-5

A: 296* B: 297 A: 2.08* B: 2.12 5 II-6

447 2.12 5 II-7

A: 283* B: 283 A: 1.89* B: 1.93 5 II-8

461 2.26 5 II-9

260 2.01 1 II-10

389 2.74 1 II-11

383 2.58 1

TABLE 65 II-12

377 2.95 1 II-13

302 1.98 1 II-14

449 2.78 1 II-15

391 2.50 1 II-16

409 2.58 1 II-17

411 2.55 1 II-18

368 2.94 1 II-19

359 2.25 1 II-20

303 1.24 1 II-21

445 1.56 1

TABLE 66 II-22

289 1.70 1 II-23

304 1.06 1 II-24

252 1.57 1

TABLE 67 No. Chamical Structure Chirality NMR II-25

¹H-NMR (DMSO-d₆) δ: 2.53 (s, 3H), 2.54 (s, 3H), 2.61 (s, 3H), 7.09 (s,1H), 7.77 (d, J = 8.88 Hz, 2H), 7.96 (d, J = 8.88 Hz, 2H), 10.8 (s, 1H).II-26

¹H-NMR (DMSO-d₆) δ: 2.52 (s, 3H), 2.60 (s, 3H), 7.00 (s, 1H), 7.38 (d, J= 8.62 Hz, 2H), 7.68 (d, J = 8.62 Hz, 2H), 10.5 (s, 1H). II-27

¹H-NMR (DMSO-d₆) δ: 2.52 (s, 3H), 2.60 (s, 3H), 6.96 (s, 1H), 7.10-7.25(m, 2H), 7.60-7.75 (m, 2H), 10.4 (s, 1H). II-28

¹H-NMR (DMSO-d₆) δ: 2.51 (s, 3H), 2.59 (s, 3H), 2.85 (s, 6H), 6.74 (m,2H), 6.82 (s, 1H), 7.43 (m, 2H), 9.92 (s, 1H). II-29

¹H-NMR (DMSO-d₆) δ: 2.51 (s, 3H), 2.59 (s, 3H), 3.73 (s, 3H), 6.88 (s,1H), 6.92 (m, 2H), 7.55 (m, 2H), 10.1 (s, 1H). II-30

¹H-NMR (DMSO-d₆) δ: 2.52 (s, 3H), 2.60 (s, 3H), 6.96 (s, 1H), 6.97 (m,1H), 7.33 (t, J = 7.86 Hz, 2H), 7.65 (d, J = 8.11 Hz, 2H), 10.1 (s, 1H).

TABLE 68 LC/MS No. Chamical Structure Chirality [M + H] RT method II-31

363 1.46 1 II-32

305 1.42 1 II-33

352 2.02 1 II-34

290 1.48 1 II-35

316 2.03 1 II-36

350 2.24 1 II-37

294 2.09 1 II-38

280 1.91 1 II-39

racemic 332 1.57 1 II-40

289 0.92 1

TABLE 69 II-41

289 0.86 1 II-42

racemic 319 1.53 1 II-43

racemic 483 2.15 1 II-44

racemic 469 2.21 1 II-45

racemic 476 1.26 1 II-46

racemic 477 1.82 1 II-47

332 2.00 1 II-48

racemic 378 2.20 1 II-49

342 2.23 1 II-50

racemic 422 2.76 1

TABLE 70 II-51

409 2.50 1* Two kinds of peaks are detected in relation to stereoisomer.

Test Example 1 TRPV4 Inhibitory Activity (IC₅₀ Value)

For each compound, TRPV4 inhibitory activity was measured using cells.

(Method) The procedures of evaluating TRPV4 inhibitory activity of acompound are as follows.

(1) TRPV4 inhibitory activity was measured using CHO-K1 cells stablyexpressing human TRPV4 (hTRPV4/CHO cells).

(2) In the day before the experimental day, frozen cell were thawed andwashed with the culture medium (MEM-α, 10% FBS, 2 mmol/L GlutaMax, 50unit Penicillin, 50 μg/mL Streptomycin). Then, cells were suspended inthe culture medium.

(3) The 384-well plates which hTRPV4/CHO cells were seeded at densitiesof 4000 cells/well in the culture medium and cultured in a CO₂ incubatorin the presence of 5% CO₂ at 37° C. for 24 hours was used as assayplates.

(4) The assay plate was washed with assay buffer (Hanks, 20 mmol/LHEPES, 2.5 mmol/L probenecid, pH7.4), and the buffer were remained at 20μL/well.

(5) 10 μl of dye loading buffer (9 μmol/L Fluo 4-AM, 0.09% PluronicF-127/assay buffer) was added to each well, then the assay plate wasincubated in a CO₂ incubator in the presence of 5% CO₂ at 37° C. for onehour. (final conc.; 3 μmol/L Fluo4-AM).

(6) The assay plate was washed with the assay buffer, and the bufferswere remained at 20 μL/well. Then the assay plate was incubated for 10min at room temperature.

(7) 20 μL of diluted compound solution was added to each well of assayplate, and mixed with built-in Pipette and Mixer of the Fluorescenceanalysis system FLIPR TETRA (Molecular devices).

(8) After incubation for 5 min, 20 μL of 4α-PDD solution was applied toeach well of assay plate and mixed with FLIPR TETRA. (final conc.; 1μmol/L 4α-PDD)

(9) The fluorescent intensity was measured with FLIPR TETRA system for10 min from the point of time addition the compound solution, at Ex470-495 nm, Em 515-575 nm wavelength.

TRPV4 inhibitory activity (IC₅₀ value) of a compound was calculatedaccording to the following procedure.

(10) In the presence of the compound, the difference between maximal andminimal of fluorescent intensity value for 5 min from just beforeaddition of 4α-PDD solution was calculated, and it was referred asMax-Min value. Max-Min value of the Ruthenium Red at 20 μM was definedas 100% inhibitory activity, Max-Min value in the absence of thecompound was defined as 0% inhibitory activity. TRPV4 inhibitoryactivity of the compound was calculated by the following formula.

(1−(Max−Min value of the compound−100% inhibitory activity)/(0%inhibitory activity−100% inhibitory activity))×100

(11) Inhibitory activity was calculated at 10 points with three foldserial dilution, in the final concentration of the compound from 10μmol/L to 0.5 nmol/L, the IC₅₀ value (nmol/L) was calculated by logisticapproximation method.

(Results)

I-156: 30 nmol/LI-297: 22 nmol/LI-382: 22 nmol/LI-521: 1.6 nmol/L

Test Example 2 TRPV4 Inhibitory Activity (IC₅₀ Value)

For each compound, TRPV4 inhibitory activity was measured using cells.

(Method) The procedures of evaluating TRPV4 inhibitory activity of acompound are as follows.

(1) TRPV4 inhibitory activity was measured using CHO-K1 cells stablyexpressing human TRPV4 (hTRPV4/CHO cells).

(2) In the day before the experimental day, frozen cell were thawed andwashed with the culture medium (MEM-α, 10% FBS, 4 mmol/L L-Glutamine, 50unit Penicillin, 50 μg/mL Streptomycin). Then cells were suspended inthe culture medium.

(3) The 384-well plates which hTRPV4/CHO cells were seeded at densitiesof 4000 cells/well in the culture medium and cultured in a CO₂ incubatorin the presence of 5% CO₂ at 37° C. for 24 hours was used as assayplates.

(4) The assay plate was washed with assay buffer (Hanks, 20 mmol/LHEPES, 2.5 mmol/L probenecid, pH7.4), and the buffer were remained at 20μL/well.

(5) 10 μl of dye loading buffer (9 μmol/L Fluo 3-AM, 0.09% PluronicF-127, 1% BSA/assay buffer) was added to each well, then the assay platewas incubated in a CO₂ incubator in the presence of 5% CO₂ at 37° C. forone hour. (final conc.; 3 μmol/L Fluo3-AM).

(6) The assay plate was washed with the assay buffer, and the bufferswere remained at 20 μL/well. Then the assay plate was incubated for 10min at room temperature.

(7) 20 μL of diluted compound solution was added to each well of assayplate, and mixed with built-in Pipette and Mixer of the Fluorescenceanalysis system FLIPR 384 (Molecular devices).

(8) After incubation for 4 min, 25 μL of 4α-PDD solution were applied toeach well of assay plate and mixed with the FLIPR TETRA. (final conc.;600 nmol/L 4α-PDD)

(9) The fluorescent intensity was measured with FLIPR TETRA system for 7min from the point of time addition the compound solution, at Ex 488 nm,Em 510-570 nm wavelength.

TRPV4 inhibitory activity (IC₅₀ value) of a compound was calculatedaccording to the following procedure.

(10) In the presence of the compound, the difference between maximal andminimal of fluorescent intensity value for 3 min from just beforeaddition of 4α-PDD solution was calculated, and it was referred asMax-Min value. Max-Min value of the Ruthenium Red at 20 μM was definedas 100% inhibitory activity, Max-Min value in the absence of thecompound was defined as 0% inhibitory activity. TRPV4 inhibitoryactivity of the compound was calculated by the following formula.

(1−(Max−Min value of the compound−100% inhibitory activity)/(0%inhibitory activity−100% inhibitory activity))×100

(11) Inhibitory activity was calculated at 10 points with twice serialdilution, in the final concentration of the compound from 3.85 μg/mL to7.5 ng/mL, the IC₅₀ value (nmol/L) was calculated by logisticapproximation method.

(Results)

II-22: 73 nmol/L

Test Example 3 TRPV4 Inhibitory Activity (IC₅₀ Value)

For each compound, TRPV4 inhibitory activity was measured using cells.

(Method) The procedures of evaluating TRPV4 inhibitory activity of acompound are as follows.

(1) TRPV4 inhibitory activity was measured using CHO-K1 cells stablyexpressing human TRPV4 (hTRPV4/CHO cells).

(2) In the day before the experimental day, frozen cell were thawed andwashed with the culture medium (MEM-α, 10% FBS, 2 mmol/L GlutaMax, 50unit Penicillin, 50 μg/mL Streptomycin). Then cells were suspended inthe culture medium.

(3) The 384-well plates which hTRPV4/CHO cells were seeded at densitiesof 4000 cells/well in the culture medium and cultured in a CO₂ incubatorin the presence of 5% CO₂ at 37° C. for 24 hours was used as assayplates.

(4) The assay plate was washed with assay buffer (Hanks, 20 mmol/LHEPES, 2.5 mmol/L probenecid, pH7.4), and the buffer were remained at 20μL/well.

(5) 10 μl of dye loading buffer (9 μmol/L Fluo4-AM, 0.09% PluronicF-127/assay buffer) was added to each well, then the assay plate wasincubated in a CO₂ incubator in the presence of 5% CO₂ at 37° C. for onehour. (final conc.; 3 μmol/L Fluo4-AM).

(6) The assay plate was washed with the assay buffer, and the bufferswere remained at 20 μL/well. Then the assay plate was incubated for 10min at room temperature.

(7) 20 μL of diluted compound solution was added to each well of assayplate, and mixed with built-in Pipette and Mixer of the Fluorescenceanalysis system FLIPR TETRA (Molecular Devices).

(8) After incubation for 5 min, 20 μL of low osmotic pressure solution(5.4 mmol/L KCl, 0.34 mmol/L Na₂HPO₄, 0.44 mmol/L KH₂PO₄, 0.41 mmol/LMgSO₄, 0.49 mmol/L MgCl₂, 1.26 mmol/L CaCl₂, 5.6 mmol/L Glucose, 20mmol/L HEPES, 2.5 mmol/L probenecid, 0.1% Pluronic F-127) were appliedto each well of assay plate and mixed with the FLIPR TETRA. (finalosmotic pressure: 218 mOsm)

(9) The fluorescent intensity was measured with FLIPR TETRA system for 5min from the point of time addition the compound solution, at Ex 470-495nm, Em 515-575 nm wavelength.

TRPV4 inhibitory activity (IC₅₀ value) of a compound was calculatedaccording to the following procedure.

(10) In the presence of the compound, the difference between maximal andminimal of fluorescent intensity value for 5 min from just beforeaddition of low osmotic pressure solution was calculated, and it wasreferred as Max-Min value. Max-Min value of the Ruthenium Red at 20 μMwas defined as 100% inhibitory activity, Max-Min value in the absence ofthe compound was defined as 0% inhibitory activity. TRPV4 inhibitoryactivity of the compound was calculated by the following formula.

(1−(Max−Min value of the compound−100% inhibitory activity)/(0%inhibitory activity−100% inhibitory activity))×100

(11) Inhibitory activity was calculated at 10 points with third serialdilution, in the final concentration of the compound from 10 μmol/L to0.5 nmol/L, the IC₅₀ value (nmol/L) was calculated by logisticapproximation method.

Test Example 4 TRPV4 Inhibitory Activity (Ki Value)

For each compound, TRPV4 inhibitory activity was measured using cells.

(Method) The procedures of evaluating TRPV4 inhibitory activity of acompound are as follows.

(1) TRPV4 inhibitory activity was measured using CHO-K1 cells stablyexpressing human TRPV4 (hTRPV4/CHO cells).

(2) Cells were subcultured using the MEM-α medium (SIGMA M4526: 500 ml),FBS (HyCloneSH30070.03: 10%), L-Glutamine 200 mmol/L (GIBCO: 4 mmol/L),P/S (nacalai tesque: 1%), G418 (nacalai tesque: 1 mg/mL).

(3) The 96-well plates which hTRPV4/CHO cells were seeded at densitiesof 2×10⁴ cells/well in the culture medium in the day before theexperimental day, and cultured in a CO₂ incubator in the presence of 5%CO₂ at 37° C. for 24 hours was used as assay plates.

(4) Cells were washed with assay buffer (Hank's Balanced Salt Solution9.8 g, 1 mol/L HEPES (pH7.5), 250 mmol/L probenecid).

(5) Fluo-3, fluorescent dye for Ca influx assay was added to each well,then the assay plate was incubated in a CO₂ incubator in the presence of5% CO₂ at 37° C. for one hour (final conc.; 5 μmol/L Fluo-3).

(6) The assay plate was washed with the assay buffer, and the buffer wasremained at 30 μL/well. Then the assay plate was incubated for 10 min at37° C.

(7) 20 μL of diluted compound solution was added to each well of assayplate, and mixed with built-in Pipette and Mixer of the fluorescenceanalysis system FDSS 3000 (Hamamatsu Photonics).

(8) 50 μL of 4α-PDD solution (concluding 0.1% Pluronic F-127) wasapplied to each well of assay plate and mixed.

(9) The fluorescent intensity was measured by FDSS 3000 for 8 min fromthe point of time addition the compound solution, at Ex 480 nm, Em 540nm wavelength.

TRPV4 inhibitory activity (Ki value) of a compound was calculatedaccording to the following procedure.

(10) In the presence of the compound, the difference between maximal andminimal of fluorescent intensity value for 8 min from just beforeaddition of 4α-PDD solution was calculated, and it was referred asMax-Min value. Max-Min value of the Ruthenium Red at 10 μM was definedas 100% inhibitory activity, Max-Min value in the absence of thecompound was defined as 0% inhibitory activity. TRPV4 inhibitoryactivity of the compound was calculated by the following formula.

(1−(Max−Min value of the compound−100% inhibitory activity)/(0%inhibitory activity−100% inhibitory activity))×100

(11) By the following formula, inhibitory activity was calculated at 10points with three fold serial dilution, in the final concentration ofthe compound from 10 μmol/L to 0.5 nmol/L. The IC₅₀ value was calculatedby dose-response curve.

100−[(fluorescent intensity in the presence of the compound−fluorescentintensity of back ground)/(total fluorescent intensity−fluorescentintensity of back ground)]×100

(12) In the presence of the compound, activity of 4α-PDD was measured at9 points with three fold serial dilution from 20 μmol/L. Activity of4α-PDD was calculated by the following formula.

(Max−Min value of the each 4α-PDD concentration−0% activity)/(100%activity−0% activity))×100

(13) Effective activity was calculated in 4α-PDD the above. The EC₅₀value was calculated by dose-response curve.

(14) The Ki value of a compound was calculated by the following formula.

Ki=IC ₅₀ value/1+([A]/EC ₅₀)

[A]: Concentration of agonist (nmol/L)

(Results)

I-20: 34.4 nmol/L

The results of the compounds of the invention (Test Examples 1, 2, and4) are shown in the following table. As for IC₅₀ value, value from 0nmol/L to below 100 nmol/L is represented as “A”, value from 100 nmol/Lto below 1000 nmol/L is represented as “B”, and value from 1000 nmol/Lto below 8000 nmol/L is represented as “C”. As for Ki value, value from0 nmol/L to below 100 nmol/L is represented as “D”, value from 100nmol/L to below 1000 nmol/L is represented as “E”, and value from 1000nmol/L to below 3000 nmol/L is represented as “F”.

TABLE 71 Test 1 Test 2 Test 4 IC50 IC50 Ki No. (nmol/L) (nmol/L)(nmol/L) I-1 E I-2 B E I-3 B E I-4 A D I-5 E I-6 F I-7 E I-8 E I-9 EI-10 E I-11 E I-12 E I-13 A E I-14 A D I-15 E I-16 E I-17 C E I-18 B DI-19 A D I-20 D I-21 D I-22 D I-23 B D I-24 B E I-25 E I-26 E I-27 B DI-28 E I-29 B E I-30 C I-31 A D I-32 B D I-33 E I-34 B D I-35 A D I-36 AD I-37 F I-38 D I-39 E I-40 E I-41 E I-42 F I-43 A D I-44 E I-45 E I-46A D I-47 C E I-48 D I-49 A D I-50 B D I-51 F I-52 D I-53 B E I-54 D I-55D I-56 E I-57 E I-58 D I-59 B E I-60 C I-61 B I-62 C I-63 C I-64 B I-65C I-66 C I-67 C I-68 C I-69 C I-70 C I-71 C I-72 C I-73 C I-74 C I-75 CI-76 A I-77 A I-78 A I-79 B I-80 B I-81 C I-82 C I-83 C I-84 C I-85 CI-86 C I-87 C I-88 C I-89 C I-90 C I-91 C I-92 B I-93 B I-94 B I-95 BI-96 B I-97 B I-98 B I-99 A I-100 A I-101 C I-102 B I-103 C I-104 AI-105 C I-106 C I-107 B I-108 C I-109 C I-110 B I-111 C I-112 C I-113 CI-114 C I-115 C I-116 C I-117 B I-118 B I-119 C I-120 C I-121 B I-122 BI-123 C I-124 A I-125 C I-126 C I-127 B I-128 B I-129 B I-130 B I-131 BI-132 A I-133 C I-134 A I-135 C I-136 A I-137 B I-138 C I-139 B I-140 CI-141 A I-142 A I-143 B I-144 B I-145 A I-146 A I-147 A I-148 B I-149 AI-150 A I-151 B I-152 B I-153 C I-154 B I-155 B I-156 A I-157 B I-158 AI-159 A I-160 A I-161 A I-162 A I-163 A I-164 B I-165 B I-166 B I-167 CI-168 B I-169 A I-170 B I-171 B I-173 B I-174 A I-175 B I-176 A I-177 BI-178 B I-179 C I-180 A I-181 C

TABLE 72 Test 1 Test 2 Test 4 IC50 IC50 Ki No. (nmol/L) (nmol/L)(nmol/L) I-182 C I-183 B I-184 A I-185 A I-186 A D I-187 C I-188 C I-189C I-190 A I-191 A I-192 C I-193 C I-194 C I-195 A I-196 A I-197 B I-198B I-199 B I-200 C I-201 A I-202 A I-203 C I-204 A I-205 B I-206 B I-207B I-208 A I-209 C I-210 A I-211 B I-212 A I-213 B I-214 B I-215 B I-216B I-217 C I-218 A I-219 E I-220 E I-221 D I-222 D I-223 B E I-224 B DI-225 A D I-226 B D I-227 E I-228 E I-229 D I-230 D I-231 E I-232 EI-233 F I-234 F I-235 A I-236 B I-237 B I-238 A I-239 B I-240 C I-241 BI-242 A I-243 B I-244 B I-245 A I-246 A I-247 C I-248 C I-249 B I-250 AI-251 C I-252 C I-253 B I-254 A I-255 C I-256 C I-257 B I-258 A I-259 AI-260 A I-261 B I-262 A I-263 B I-264 A I-265 B I-266 B I-267 C I-268 BI-269 C I-270 B I-271 A I-272 A I-273 A I-274 C I-275 C I-276 A I-277 AI-278 A I-279 C I-280 A I-281 B I-282 B I-283 C I-284 B I-285 B I-286 AI-287 A I-288 A I-289 B I-290 A I-291 B I-292 A I-293 A I-294 C I-295 BI-296 C I-297 A I-298 C I-299 C I-300 C I-301 A I-302 A I-303 B I-304 BI-305 B I-306 A I-307 A I-308 B I-309 A I-310 A I-311 A I-312 B I-313 AI-314 A I-315 A I-316 A I-317 C I-318 A I-319 B I-320 A I-321 B I-322 BI-323 A I-324 B I-325 B I-326 A I-327 A I-328 A I-329 A I-330 A I-331 AI-332 B I-333 C I-334 A I-335 A I-336 B I-337 C I-338 B I-339 C I-340 BI-341 A I-342 B I-343 A I-344 B I-345 A I-346 A I-347 B I-348 A I-349 BI-350 A I-351 C I-352 A I-353 A I-354 A I-355 B I-356 B I-357 A I-358 BI-359 A I-360 A I-361 C I-362 C I-363 B I-364 C I-365 A I-366 A I-367 AI-368 A I-369 A I-370 A I-371 B I-372 B I-373 A I-374 C I-375 A I-376 CI-377 A I-378 B I-379 A I-380 B I-381 B I-382 A I-383 B I-384 B I-385 BI-386 C I-387 B I-388 A I-389 A I-390 A I-391 B I-392 A I-393 B I-394 AI-395 A I-396 A I-397 B I-398 C I-399 C I-400 B I-401 B I-402 B I-403 BI-404 B I-405 A I-406 C I-407 B I-408 A I-409 B I-410 A I-411 B I-412 CI-413 B I-414 C I-415 B I-416 A I-417 A I-418 A I-419 C I-420 C I-421 CI-422 B I-423 A I-424 A I-425 B I-426 C I-427 B I-428 B I-429 C I-430 BI-431 C I-432 B I-433 B I-434 A I-435 A I-436 B I-437 A I-438 A I-439 AI-440 B I-441 B I-442 B I-443 A I-444 A I-445 C I-446 C I-447 A I-448 AI-449 A I-450 A I-451 B I-452 C I-453 B I-454 A I-455 A I-456 A I-457 AI-458 A I-459 B I-460 C I-461 B I-462 B I-463 B I-464 C I-465 B I-466 BI-467 A I-468 A I-469 A I-470 A I-471 A I-472 C I-473 B I-474 B I-475 BI-476 A I-477 C I-478 B I-479 C I-480 C I-481 B

TABLE 73 Test 1 Test 2 Test 4 IC50 IC50 Ki No. (nmol/L) (nmol/L)(nmol/L) I-482 B I-483 B I-484 A I-485 B I-486 B I-487 B I-488 A I-489 AI-490 A I-491 C I-492 A I-493 B I-494 B I-495 B I-496 A I-497 A I-498 AI-499 A I-500 B I-501 A I-502 A I-503 A I-504 A I-505 A I-506 A I-507 AI-508 A I-509 B I-510 A I-511 C I-512 A I-513 A I-514 C I-515 B I-516 AI-517 A I-518 A I-519 A I-520 C I-521 A I-522 A I-523 A I-524 A I-525 AI-526 A I-527 A I-528 A I-529 B I-530 A I-531 A I-532 A I-533 A I-534 AI-535 E I-536 D I-537 C I-538 C I-539 A I-540 B I-541 A I-542 B I-543 BI-544 C I-545 B I-546 B I-547 A I-548 B I-549 C I-550 B I-551 B I-552 BII-1 F II-2 C II-3 B II-4 C II-5 B II-6 B II-7 C II-8 B II-9 C II-10 CII-11 C II-12 C II-13 C II-14 C II-15 C II-16 B II-17 C II-18 C II-19 BII-20 B II-21 C II-22 A II-23 C II-24 C II-25 E II-26 E II-27 E II-28 EII-29 E II-30 E II-31 C II-32 A II-33 C II-34 A II-35 A II-36 A II-37 AII-38 A II-39 B II-40 B II-41 C II-43 C II-44 C II-45 C II-46 C II-47 BII-48 A II-49 A II-50 B II-51 C

Test Example 5 CYP3A4 Fluorescent MBI Test

The CYP3A4 fluorescent MBI test is a test of investigating enhancementof CYP3A4 inhibition of a compound of the present invention by ametabolism reaction, and the test was performed using, as CYP3A4 enzymeexpressed in Esherichia coli and employing, as an index, a reaction inwhich 7-benzyloxytrifluoromethylchmarin (7-BFC) is debenzylated by theCYP3A4 enzyme to produce a metabolite, 7-hydroxytrifluoromethylchmarin(HFC) emitting fluorescent light.

The reaction conditions were as follows: substrate, 5.6 μmol/L 7-BFC;pre-reaction time, b or 30 minutes; reaction time, 15 minutes; reactiontemperature, 25° C. (room temperature); CYP3A4 content (expressed inEscherichia coli), at pre-reaction 62.5 μmol/mL, at reaction 6.25μmol/mL (at 10-fold dilution); concentration of the compound of thepresent invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol/L (six points).

An enzyme in a K-Pi buffer (pH 7.4) and a solution of the compound ofthe present invention as a pre-reaction solution were added to a 96-wellplate at the above composition of the pre-reaction. A part of it wastransferred to another 96-well plate so that it was 1/10 diluted by asubstrate in a K-Pi buffer. NADPH as a co-factor was added to initiate areaction as an index (without preincubation) and, after a predeterminedtime of a reaction, acetonitrile/0.5 mol/L Tris(trishydroxyaminomethane)=4/1 (V/V) was added to stop the reaction. Inaddition, NADPH was added to a remaining preincubation solution toinitiate a preincubation (with preincubation) and, after a predeterminedtime of a preincubation, a part was transferred to another plate so thatit was 1/10 diluted with a substrate and a K-Pi buffer to initiate areaction as an index. After a predetermined time of a reaction,acetonitrile/0.5 mol/L Tris (trishydroxyaminomethane)=4/1 (V/V) wasadded to stop the reaction. For the plate on which each index reactionhad been performed, a fluorescent value of 7-HFC which is a metabolitewas measured with a fluorescent plate reader. (Ex=420 nm, Em=535 nm).

Addition of only DMSO which is a solvent dissolving the compound of thepresent invention to a reaction system was adopted as a control (100%).Remaining activity (%) was calculated at each concentration of thecompound of the present invention added as the solution, and IC₅₀ wascalculated by reverse-presumption by a logistic model using aconcentration and an inhibition rate. When a difference between IC₅₀values is 5 μM or more, this was defined as (+) and, when the differenceis 3 μM or less, this was defined as (−).

(Results) I-107: (−) I-131: (−) Test Example 6 CYP Inhibition Test

Using commercially available pooled human hepatic microsome, andemploying, as markers, 7-ethoxyresorufin O-deethylation (CYP1A2),tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4′-hydroxylation(CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenedinehydroxylation (CYP3A4) as typical substrate metabolism reactions ofhuman main five CYP enzyme forms (CYP1A2, 2C9, 2C19, 2D6, 3A4), aninhibitory degree of each metabolite production amount by a compound ofthe present invention was assessed.

The reaction conditions were as follows: substrate, 0.5 μmol/Lethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/LS-mephenytoin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 μmol/Lterfenedine (CYP3A4); reaction time, 15 minutes; reaction temperature,37° C.; enzyme, pooled human hepatic microsome 0.2 mg protein/mL;concentration of the compound of the present invention, 1, 5, 10, 20μmol/L (four points).

Each five kinds of substrates, human hepatic microsome, and the compoundof the present invention in 50 mmol/L Hepes buffer as a reactionsolution were added to a 96-well plate at the composition as describedabove. NADPH, as a cofactor was added to initiate metabolism reactionsas markers and, after the incubation at 37° C. for 15 minutes, amethanol/acetonitrile=1/1 (v/v) solution was added to stop the reaction.After the centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2metabolite) in the supernatant was quantified by a fluorescentmultilabel counter and toltributamide hydroxide (CYP2C9P metabolite),mephenytoin 4′ hydroxide (CYP2C19 metabolite), dextromethorphan (CYP2D6metabolite), and terfenadine alcohol (CYP3A4 metabolite) were quantifiedby LC/MS/MS.

Addition of only DMSO being a solvent dissolving the compound of thepresent invention to a reaction system was adopted as a control (100%).Remaining activity (%) was calculated at each concentration of thecompound of the present invention added as the solution and IC₅₀ wascalculated by reverse presumption by a logistic model using aconcentration and an inhibition rate.

(Results)

I-17: five kinds >20 μmol/LI-42: five kinds >20 μmol/LI-95: five kinds >20 μmol/LI-107: five kinds >20 μmol/LI-116: five kinds >20 μmol/L

Test Example 7 FAT Test

Mutagenicity of a compound of the present invention was evaluated.

20 L of freezing-stored rat typhoid bacillus (Salmonella typhimuriumTA98 strain, TA100 strain) was inoculated on 10 mL of a liquid nutrientmedium (2.5% Oxoid nutrient broth No. 2), and this was cultured beforeshaking at 37° C. for 10 hours. 9 mL of a bacterial solution of the TA98strain was centrifuged (2000×g, 10 minutes) to remove a culturingsolution. The bacteria was suspended in 9 mL of a Micro F buffer(K₂HPO₄: 3.5 g/L, KH₂PO₄: 1 g/L, (NH₄)₂SO₄: 1 g/L, trisodium citratedehydrate: 0.25 g/L, MgSO₄*7H₂O: 0.1 g/L), the suspension was added to110 mL of an Exposure medium (Micro F buffer containing Biotin: 8 μg/mL,histidine: 0.2 μg/mL, glucose: 8 mg/mL). The TA100 strain was added to120 mL of the Exposure medium relative to 3.16 mL of the bacterialsolution to prepare a test bacterial solution. Each 12 μL of DMSOsolution of the compound of the present invention (several stagedilution from maximum dose 50 mg/mL at 2 to 3 fold ratio), DMSO as anegative control, and 50 μg/mL of 4-nitroquinoline-1-oxide DMSO solutionfor the TA98 strain under the non-metabolism activating condition as apositive control, 0.25 μg/mL of2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100strain under the non-metabolism activating condition as a positivecontrol, 40 μg/mL of 2-aminoanthracene DMSO solution for the TA98 strainunder the metabolism activating condition as a positive control, 20μg/mL of 2-aminoanthracene DMSO solution for the TA100 strain under themetabolism activating condition as a positive control, and 588 μL of thetest bacterial solution (a mixed solution of 498 μL of the testbacterial solution and 90 μL of S9 mix under the metabolism activatingcondition) were mixed, and this was shaking-cultured at 37° C. for 90minutes. 460 μL of the bacterial solution exposed to the compound of thepresent invention was mixed with 2300 μL of an Indicator medium (Micro Fbuffer containing Biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8mg/mL, Bromo Cresol Purple: 37.5 μg/mL), each 50 μL was dispensed intomicroplate 48 wells/dose, and this was subjected to stationary culturingat 37° C. for 3 days. Since a well containing a bacterium which hasobtained the proliferation ability by mutation of an amino acid(histidine) synthesizing enzyme gene turns from purple to yellow due toa pH change, the bacterium proliferation well which has turned to yellowin 48 wells per dose was counted, and was assessed by comparing with anegative control group. (−) means that mutagenicity is negative and (+)is positive.

(Results) I-18: (−) I-131: (−) Test Example 8 Solubility Test

The solubility of a compound of the present invention was determinedunder 1% DMSO addition conditions. A 10 mmol/L solution of the compoundwas prepared with DMSO, and 6 μL of the solution of the compound of thepresent invention was added to 594 μL of an artificial intestinal juice(water and 118 mL of 0.2 mol/L NaOH reagent were added to 250 mL of 0.2mol/L potassium dihydrogen phosphate reagent to reach 1000 mL) with a pHof 6.8. The mixture was left standing for 16 hours at 25° C., and themixture was vacuum-filtered. The filtrate was two-fold diluted withmethanol/water=1/1 (V/V), and the compound concentration in the filtratewas measured with HPLC or LC/MS/MS by the absolute calibration method.

(Results)

I-17: >50 μmol/LI-18: >50 μmol/LI-81: >50 μmol/LII-1: >50 μmol/L

Test Example 9 Metabolism Stability Test

Using a commercially available pooled human hepatic microsomes, acompound of the present invention was reacted for a constant time, aremaining rate was calculated by comparing a reacted sample and anunreacted sample, thereby, a degree of metabolism in liver was assessed.

A reaction was performed (oxidative reaction) at 37° C. for 0 minute or30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/Lmagnesium chloride) containing 0.5 mg protein/mL of human livermicrosomes. After the reaction, 50 μL of the reaction mixture was addedto 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at3000 rpm for 15 minutes. The compound of the present invention in thesupernatant was quantified by LC/MS/MS, and a remaining amount of thecompound of the present invention after the reaction was calculated,letting a compound amount at 0 minute reaction time to be 100%.Hydrolysis reaction was performed in the absence of NADPH andglucuronidation reaction was in the presence of 5 mmol/L UDP-glucuronicacid in place of NADPH, followed by similar operations.

(Results) Compound concentration: 0.5 μmol/L

I-17: 92.2% I-18: 86.4% I-95: 99.4% Test Example 10 hERG Test

For the purpose of assessing risk of an electrocardiogram QT intervalprolongation of a compound of the present invention, effects of thecompound of the present invention on delayed rectifier K⁺ current(I_(Kr)), which plays an important role in the ventricularrepolarization process, was studied using HEK293 cells expressing humanether-a-go-go related gene (hERG) channel.

After a cell was retained at a membrane potential of −80 mV by wholecell patch clamp method using an automated patch clamp system(PatchXpress 7000A, Axon Instruments Inc.), I_(Kr) induced bydepolarization pulse stimulation at +40 mV for 2 seconds and, further,repolarization pulse stimulation at −50 mV for 2 seconds was recorded.After the generated current was stabilized, extracellular solution(NaCl: 135 mmol/L, KCl: 5.4 mmol/L, NaH₂PO₄: 0.3 mmol/L, CaCl₂.2H₂O: 1.8mmol/L, MgCl₂.6H₂O: 1 mmol/L, glucose: 10 mmol/L, HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH=7.4)in which the compound of the present invention had been dissolved at anobjective concentration was applied to the cell under the roomtemperature condition for 10 minutes. From the recording I_(Kr), anabsolute value of the tail peak current was measured based on thecurrent value at the resting membrane potential using an analysissoftware (DataXpress ver. 1, Molecular Devices Corporation). Further,the % inhibition relative to the tail peak current before application ofthe compound of the present invention was calculated, and compared withthe vehicle-applied group (0.1% dimethyl sulfoxide solution) to assessinfluence of the compound of the present invention on I_(Kr).

(Results) % inhibition was shown at 1 μmol/L of the compound.

I-18: 6.1%

Test Example 11 BA Test

Materials and methods for experiments to evaluate oral absorbability

(1) Experimental animals: rats or mice were used.(2) Breeding condition: rats or mice were allowed free access to solidfeed and sterilized tap water(3) Setting of dosage and grouping: Oral administration and intravenousadministration were performed with the predetermined dosage. Groupingwas set as below. (Dosage varied depending on each compound)

Oral administration 1 to 30 mg/kg (n=2 to 3)

Intravenous administration 0.5 to 10 mg/kg (n=2 to 3)

(4) Preparation of administered liquid: Oral administration wasperformed using a solution or a suspension. Intravenous administrationwas performed after solubilization.(5) Method of Administration: In oral administration, compulsoryadministration to the stomach was conducted using an oral sonde. Inintravenous administration, administration from the caudal vein wasconducted using a syringe with an injection needle.(6) Evaluation items: Blood was chronologically collected, and thenconcentration of a compound of the present invention in blood plasma wasmeasured using a LC/MS/MS.

Area Under the Blood Concentration-Time Curve

(7) Statistical analysis: With regard to a shift in plasma concentrationof the compound of the present invention, the area under the plasmaconcentration-time curve (AUC) was calculated using a nonlinearleast-squares program, WinNonlin (a registered trademark).Bioavailability (BA) was calculated from the AUCs of the oraladministration group and the intravenous administration group.(Results) Mouse, Oral administration 1 mg/kg

I-17: 54.6% I-131: 61.4% Formulation Example 1

A granule containing the following ingredient is prepared.

Ingredient Compound represented by any of the  10 mg formula (I), (II),or (III) Lactose 700 mg Corn starch 274 mg HPC-L  16 mg

The compound represented by any of the formula (I), (II), or (III), andlactose are passed through a 60 mesh sieve. Corn starch is passedthrough a 120 mesh sieve. These are mixed with a V-type mixing machine.An aqueous solution of HPC-L (low viscosity hydroxypropylcellulose) isadded to a mixture powder, and this is kneaded, granulated (extrusiongranulation, pore diameter 0.5 to 1 mm), and dried. The resulting drygranule is sieved with a vibration sieve (12/60 mesh) to obtain agranule.

Formulation Example 2

A powder for filling into a capsule containing the following ingredientsis prepared.

Ingredient Compound represented by any of the 15 mg formula (I), (II),or (III) Lactose 90 mg Corn starch 42 mg HPC-L  3 mg

The compound represented by any of the formula (I), (II), or (III), andlactose are passed through a 60 mesh sieve. Corn starch is passedthrough a 120 mesh sieve. These and HPC-L are mixed, kneaded,granulated, and dried. The resulting dry granule is granulate, then 150mg of them is filled into a No. 4 hard gelatin capsule.

Formulation Example 3

A tablet containing the following ingredients is prepared.

Ingredient Compound represented by any of the 10 mg formula (I), (II),or (III) Lactose 90 mg Microcrystaline cellulose 30 mg CMC-Na 15 mgMagnesium stearate  5 mg

The compound represented by any of the formula (I), (II), or (III),lactose, microcrystalline cellulose, CMC-Na (carboxymethylcellulosesodium salt) are passed through a 60 mesh sieve, and mixed. Magnesiumstearate is mixed into a mixture powder to obtain a mixture powder fortabletting. The present mixed powder is directly compressed to obtain a150 mg tablet.

Formulation Example 4

The following ingredients are warmed, mixed, and sterilized to obtain aninjectable.

Ingredient Compound represented by any of the  3 mg formula (I), (II),or (III) Nonionic surfactant 15 mg Purified water for injection  1 ml

A cataplasm containing the following ingredients is prepared.

Ingredient Compound represented by any of the formula (I), (II), or(III)  50 mg aqueous-based (5% ethanol/5% butylene glycol/90% purifiedwater) 950 mg glycerin kaoline aqueous polyvinyl alcohol

The compound represented by any of the formula (I), (II), or (III) isadded to aqueous-based. The mixture is irradiated by ultrasonic for 15minutes and then is sufficiently stirred to obtain a solution. 5 part ofglycerin, 1 part of kaoline and 5 part of aqueous polyvinyl alcohol arehomogeneously mixed and 1 part of the resulting solution is added to theabove solution including the compound represented by any of the formula(I), (II), or (III). The obtained solution is mixed and to give a pasteform and the resulting paste is applied to an onwoven fabric. Theresulting composition is covered by polyester film to give a cataplasm.

INDUSTRIAL APPLICABILITY

The compound of the invention has TRPV4 inhibitory activity and isuseful in the treatment and/or prevention of a TRPV4 receptor-mediateddisorder such as inflammatory pain (bladder inflammatory pain, painafter tooth extraction, postoperative pain, pain in the low back,periarthritis scapulohumeralis, cervico-omo-brachial syndrome,inflammation of a tendon or a tendon sheath, osteoarthritis, chronicarticular rheumatism), neuropathic pain (sciatica, postherpeticneuralgia, diabetic neuropathy), pain related to cancer (cancer pain,bone metastasis pain, pain with the administration of anticancer agent),IBS, inflammatory bowel disease, osteoporosis, articular cartilagedegeneration, cerebral stroke, incontinence, overactive bladder, urinarydisturbance by bladder inflammation, asthma, dry skin, atopicdermatitis, metastasis and invasion of cancer, corneal ulcer, obesity,insulin resistance, diabetes, or the like.

1. A compound of formula (I):

wherein: R¹ is a hydrogen atom, substituted or unsubstituted alkyl,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, or substituted or unsubstituted non-aromaticheterocyclyl; —X— is —N(R³)— or —S—; ═Y— is ═C(R⁴)— or ═N—; —Z— is—N(R⁷)—, —O—, or —S—; R² is substituted or unsubstituted alkyloxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkynyloxy, substituted or unsubstituted amino, substituted orunsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy,substituted or unsubstituted non-aromatic carbocyclyloxy, substituted orunsubstituted aromatic heterocyclyloxy, substituted or unsubstitutednon-aromatic heterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, or substituted or unsubstituted non-aromaticheterocyclylsulfanyl, or a group represented by the following formula:—(CR^(2a)R^(2b))_(n)—R^(2c) wherein R^(2a) is each independently ahydrogen atom, halogen, hydroxy, carboxy, sulfanyl, cyano, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkyloxy, substituted or unsubstituted alkenyloxy, substituted orunsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl,substituted or unsubstituted alkenylcarbonyl, substituted orunsubstituted alkynylcarbonyl, substituted or unsubstituted amino,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl; R^(2b) is each independently a hydrogen atom,halogen, hydroxy, carboxy, sulfanyl, cyano, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted alkyloxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted orunsubstituted alkenylcarbonyl, substituted or unsubstitutedalkynylcarbonyl, substituted or unsubstituted amino, substituted orunsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclyl sulfonyl; or R^(2a) and R^(2b) which are attached to thesame carbon atom may be taken together to form oxo, substituted orunsubstituted imino, a substituted or unsubstituted non-aromaticcarbocycle, or a substituted or unsubstituted non-aromatic heterocycle,or two of R^(2a) which are attached to the adjacent carbon atoms and/ortwo of R^(2b) which are attached to the adjacent carbon atoms may betaken together to form a bond; R^(2c) is a hydrogen atom, halogen,hydroxy, carboxy, sulfanyl, sulfino, sulfo, cyano, hydrazino, ureido,amidino, guanidino, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substitutedor unsubstituted alkynylcarbonyl, substituted or unsubstituted amino,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted imino, substituted or unsubstitutedalkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy,substituted or unsubstituted alkynylcarbonyloxy, substituted orunsubstituted alkyloxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted carbamoyl, substituted or unsubstitutedsulfamoyl, substituted or unsubstituted aromatic carbocyclyl,substituted or unsubstituted non-aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic heterocyclyl, substituted or unsubstituted aromaticcarbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylcarbonyl, substituted orunsubstituted non-aromatic carbocyclylcarbonyl, substituted orunsubstituted aromatic heterocyclylcarbonyl, substituted orunsubstituted non-aromatic heterocyclylcarbonyl, substituted orunsubstituted aromatic carbocyclyloxycarbonyl, substituted orunsubstituted non-aromatic carbocyclyloxycarbonyl, substituted orunsubstituted aromatic heterocyclyloxycarbonyl, substituted orunsubstituted non-aromatic heterocyclyloxycarbonyl, substituted orunsubstituted aromatic carbocyclylcarbonyloxy, substituted orunsubstituted non-aromatic carbocyclylcarbonyloxy, substituted orunsubstituted aromatic heterocyclylcarbonyloxy, substituted orunsubstituted non-aromatic heterocyclylcarbonyloxy, substituted orunsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstitutednon-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl; n is an integer from 1 to 3; R³ and R⁷ are eachindependently a hydrogen atom, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkylsulfonyl, substituted orunsubstituted alkenylsulfonyl, substituted or unsubstitutedalkynylsulfonyl, substituted or unsubstituted carbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, or substituted orunsubstituted non-aromatic heterocyclyl; R⁴ and R⁵ are eachindependently a hydrogen atom, halogen, hydroxy, carboxy, formyl,formyloxy, sulfanyl, sulfino, sulfo, cyano, nitro, azido, amidino,guanidino, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substitutedor unsubstituted alkynylcarbonyl, substituted or unsubstituted amino,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted imino, substituted or unsubstitutedalkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy,substituted or unsubstituted alkynylcarbonyloxy, substituted orunsubstituted alkyloxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl,substituted or unsubstituted carbamoyl, substituted or unsubstitutedsulfamoyl, substituted or unsubstituted aromatic carbocyclyl,substituted or unsubstituted non-aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic heterocyclyl, substituted or unsubstituted aromaticcarbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylcarbonyl, substituted orunsubstituted non-aromatic carbocyclylcarbonyl, substituted orunsubstituted aromatic heterocyclylcarbonyl, substituted orunsubstituted non-aromatic heterocyclylcarbonyl, substituted orunsubstituted aromatic carbocyclyloxycarbonyl, substituted orunsubstituted non-aromatic carbocyclyloxycarbonyl, substituted orunsubstituted aromatic heterocyclyloxycarbonyl, substituted orunsubstituted non-aromatic heterocyclyloxycarbonyl, substituted orunsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstitutednon-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl; R⁶ is a hydrogen atom, halogen, hydroxy, formyl,formyloxy, sulfanyl, thioformyl, cyano, substituted or unsubstitutedamidino, substituted or unsubstituted guanidino, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkyloxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted orunsubstituted alkenylcarbonyl, substituted or unsubstitutedalkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted alkenylsulfonyl, substituted or unsubstitutedalkynylsulfonyl, substituted or unsubstituted alkylcarbonyloxy,substituted or unsubstituted alkenylcarbonyloxy, substituted orunsubstituted alkynylcarbonyloxy, substituted or unsubstitutedalkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,substituted or unsubstituted alkynyloxycarbonyl, substituted orunsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl,substituted or unsubstituted carbamoyl, substituted or unsubstitutedsulfamoyl, substituted or unsubstituted aromatic carbocyclyl,substituted or unsubstituted non-aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic heterocyclyl, substituted or unsubstituted aromaticcarbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylcarbonyl, substituted orunsubstituted non-aromatic carbocyclylcarbonyl, substituted orunsubstituted aromatic heterocyclylcarbonyl, substituted orunsubstituted non-aromatic heterocyclylcarbonyl, substituted orunsubstituted aromatic carbocyclyloxycarbonyl, substituted orunsubstituted non-aromatic carbocyclyloxycarbonyl, substituted orunsubstituted aromatic heterocyclyloxycarbonyl, substituted orunsubstituted non-aromatic heterocyclyloxycarbonyl, substituted orunsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstitutednon-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, or substituted or unsubstituted non-aromaticheterocyclylsulfonyl; provided that compounds wherein —X— is —S—, ═Y— is═C(R⁴)—, and —Z— is —S— are excluded; and provided that the followingcompounds are excluded:

or a pharmaceutically acceptable salt thereof.
 2. The compound accordingto claim 1, wherein R¹ is a hydrogen atom, or a pharmaceuticallyacceptable salt thereof.
 3. The compound according to claim 1, wherein—Z— is —O— or —S—, or a pharmaceutically acceptable salt thereof.
 4. Thecompound according to claim 1, wherein R² is substituted orunsubstituted amino, substituted or unsubstituted aromatic carbocyclyl,substituted or unsubstituted non-aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, or substituted or unsubstitutednon-aromatic heterocyclyl, or a group represented by the followingformula: —(CR^(2a)R^(2b))_(n)—R^(2c) wherein R^(2a) is eachindependently a hydrogen atom, halogen, hydroxy, carboxy, sulfanyl,cyano, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedamino, substituted or unsubstituted alkylsulfanyl, substituted orunsubstituted alkenylsulfanyl, substituted or unsubstitutedalkynylsulfanyl, substituted or unsubstituted carbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted non-aromaticcarbocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl;R^(2b) is each independently a hydrogen atom, halogen, hydroxy, carboxy,sulfanyl, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedamino, substituted or unsubstituted alkylsulfanyl, substituted orunsubstituted alkenylsulfanyl, substituted or unsubstitutedalkynylsulfanyl, substituted or unsubstituted carbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted non-aromaticcarbocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl;R^(2a) and R^(2b) which are attached to the same carbon atom at any oneposition may be taken together to form oxo, substituted or unsubstitutedimino, a substituted or unsubstituted non-aromatic carbocycle, or asubstituted or unsubstituted non-aromatic heterocycle; R^(2c) is ahydrogen atom, halogen, hydroxy, carboxy, cyano, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted amino,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted carbamoyl, substituted or unsubstitutedsulfamoyl, substituted or unsubstituted aromatic carbocyclyl,substituted or unsubstituted non-aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic heterocyclyl, substituted or unsubstituted aromaticcarbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylsulfanyl, substituted orunsubstituted non-aromatic carbocyclylsulfanyl, substituted orunsubstituted aromatic heterocyclylsulfanyl, substituted orunsubstituted non-aromatic heterocyclylsulfanyl, substituted orunsubstituted non-aromatic carbocyclylsulfonyl, substituted orunsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstitutedaromatic heterocyclylsulfonyl, or substituted or unsubstitutednon-aromatic heterocyclylsulfonyl; n is an integer from 1 to 3; or apharmaceutically acceptable salt thereof.
 5. The compound according toclaim 1, wherein R⁴ and R⁵ are each independently a hydrogen atom,halogen, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted amino, substituted or unsubstituted carbamoyl, substitutedor unsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclylcarbonyl, substitutedor unsubstituted non-aromatic carbocyclylcarbonyl, substituted orunsubstituted aromatic heterocyclylcarbonyl, substituted orunsubstituted non-aromatic heterocyclylcarbonyl, substituted orunsubstituted aromatic carbocyclyloxycarbonyl, substituted orunsubstituted non-aromatic carbocyclyloxycarbonyl, substituted orunsubstituted aromatic heterocyclyloxycarbonyl, or substituted orunsubstituted non-aromatic heterocyclyloxycarbonyl, or apharmaceutically acceptable salt thereof.
 6. The compound according toclaim 1, wherein R⁶ is a hydrogen atom, halogen, hydroxy, sulfanyl,cyano, substituted or unsubstituted amidino, substituted orunsubstituted guanidino, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkyloxy, substituted or unsubstitutedalkenyloxy, substituted or unsubstituted alkynyloxy, substituted orunsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkyloxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl,substituted or unsubstituted alkenylsulfanyl, substituted orunsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedcarbamoyl, or substituted or unsubstituted sulfamoyl, or apharmaceutically acceptable salt thereof.
 7. A compound of formula(III):

wherein: a and b are each independently 0, 1, 2 or 3; —X— is —N(R³)— or—S—; R³ is a hydrogen atom, alkyl, or a group represented by thefollowing formula: —(C(R^(3a))(R^(3b)))_(r)—OR^(3c),—(C(R^(3a))(R^(3b)))_(r)—CN, or —(C(R^(3a))(R^(3b)))_(r)-E-(R^(3c))_(d)wherein R^(3a) is each independently a hydrogen atom, halogen, alkyl orhaloalkyl, R^(3b) is each independently a hydrogen atom, halogen, alkylor haloalkyl, or two of R^(3a) which are attached to the adjacent carbonatoms and/or two of R^(3b) which are attached to the adjacent carbonatoms may be taken together to form a bond; R^(3c) is each independentlya hydrogen atom, alkyl or haloalkyl; E is an aromatic carbocycle, anon-aromatic carbocycle, an aromatic heterocycle or a non-aromaticheterocycle; d and r are each independently 0, 1, 2 or 3; ═Y— is ═CH— or═N—; —Z— is —O— or —S—; ring A is an aromatic carbocycle, a non-aromaticcarbocycle, an aromatic heterocycle, or a non-aromatic heterocycle;R^(2d) is each independently a hydrogen atom, halogen, nitro, alkyl,haloalkyl, or a group represented by the following formula:—(C(R^(2e))(R^(2f)))_(c)—OR^(2g), —SR^(2g),—O—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d), —C(═O)—R^(2g),—C(═O)-E-(R^(2k))_(d), —(C(R^(2e))(R^(2f)))_(c)—C(═O)—OR^(2g),—C(═O)—N(R^(2g))(R^(2h)),—C(═O)—N(R^(2g))(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d),—(C(R^(2e))(R^(2f)))_(c)—SO₂R^(2g), —SO₂-E-(R^(2k))_(d),—SO₂N(R^(2g))(R^(2h)),—SO₂N(R^(2g))—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d),—(C(R^(2e))(R^(2f)))_(c)—N(R^(2g))(R^(2h)),—N(R^(2g))—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d),—N(R^(2g))—C(═O)—R^(2h), —N(R^(2g))—C(═O)-E-(R^(2k))_(d),—(C(R^(2e))(R^(2f)))_(c)—N(R^(2g))—C(═O)—OR^(2h), —N(R^(2g))—SO₂R^(2h),—N(R^(2g))—SO₂-E-(R^(2k))_(d), —(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d),—(C(R^(2e))(R^(2f)))_(c)—CN,—(C(R^(2e))(R^(2f)))_(c)—O—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d),—O—(C(R^(2e))(R^(2f)))_(c)—OR^(2g),—O—(C(R^(2e))(R^(2f)))_(c)—N(R^(2g))(R^(2h)), or—(C(R^(2e))(R^(2f)))_(c)—N(R^(2g))-E-(R^(2k))_(d), or two of R^(2d)which are attached to the same carbon atom may be taken together to formoxo; wherein c is 0, 1, 2 or 3, d is the same as the above-mentioned;R^(2e) is each independently a hydrogen atom, halogen, alkyl orhaloalkyl, R^(2f) is each independently a hydrogen atom, halogen, alkylor haloalkyl, or, two of R^(2e) which are attached to the adjacentcarbon atoms and/or two of R^(2f) which are attached to the adjacentcarbon atoms may be taken together to form a bond; R^(2g) is a hydrogenatom, alkyl or haloalkyl; R^(2h) is a hydrogen atom, alkyl or haloalkyl;R^(2k) is each independently halogen, alkyl, haloalkyl, oxo, —CN, or agroup represented by the following formula: —OR^(2m), —C(═O)—OR^(2m),—SO₂R^(2m), -E-R^(2m), or —N(R^(2m))(R^(2n)), or two of R^(2k) which areattached to the same carbon atom may be taken together to form oxo,wherein E is the same as the above-mentioned; R^(2m) is a hydrogen atom,alkyl or haloalkyl; R^(2n) is a hydrogen atom, alkyl or haloalkyl; R⁵ isa hydrogen atom, halogen, alkyl, haloalkyl, or a group represented bythe following formula: —(C(R^(5e))(R^(5f)))_(e)—OR^(5g),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))(R^(5h)),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—R^(5h),—(C((R^(5e))(R^(5f)))_(e)—C(═O)—N(R^(5g))(R^(5h)),—(C(R^(5e))(R^(5f)))_(e)—O—C(═O)—N(R^(5g))(R^(5h)),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—N(R^(5h))(R^(5k)),—(C(R^(5e))(R^(5f)))_(e)—C(═O)—R^(5g),—(C(R^(5e))(R^(5f)))_(e)—C(═O)-G-(R^(5m))_(h),—(C(R^(5e))(R^(5f)))_(e)—CN, —(C(R^(5e))(R^(5f)))_(e)-G-(R^(5m))_(h),—(C(R^(5e))(R^(5f)))^(e)—N(R^(5g))—SO₂N(R^(5h))(R^(5k)),—(C(R^(5e))(R^(5f)))_(e)—SO₂R^(5g),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—OR^(5h),(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)-G-(R^(5m))_(h),—(C(R^(5e))(R^(5f)))_(e)—C(═O)—OR^(5g),—(C(R^(5e))(R^(5f)))_(e)—C(═O)—N(R^(5g))—(CH₂)_(h)—O(R^(5h)),—(C(R^(5e))(R^(5f)))_(e)—C(═O)—N(R^(5g))—(CH₂)_(h)—N(R^(5h))(R^(5k)),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—(CH₂)—OR^(5h), or—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—(CH₂)—O—C(═O)—N(R^(5h))(R^(5k));wherein R^(5e) is each independently a hydrogen atom, halogen, alkyl orhaloalkyl, R^(5f) is each independently a hydrogen atom, halogen, alkylor haloalkyl, or two of R^(5e) which are attached to the adjacent carbonatoms and/or two of R^(5f) which are attached to the adjacent carbonatoms may be taken together to form a bond; R^(5g) is a hydrogen atom,alkyl or haloalkyl; R^(5h) is a hydrogen atom, alkyl or haloalkyl;R^(5k) is a hydrogen atom, alkyl or haloalkyl; R^(5m) is halogen, alkyl,haloalkyl, or a group represented by the following formula: —OR^(5n),—C(═O)—OR^(5n), —SO₂R^(5n), or —N(R^(5n))(R^(5p)), or two of R^(5m)which are attached to the same carbon atom may be taken together to formoxo, wherein R^(5n) is a hydrogen atom, alkyl or haloalkyl; R^(5p) is ahydrogen atom, alkyl or haloalkyl; G is an aromatic carbocycle, anon-aromatic carbocycle, an aromatic heterocycle or a non-aromaticheterocycle; e and h are each independently 0, 1, 2 or 3; R⁶ is ahydrogen atom, halogen, alkyl, haloalkyl, alkenyl, amidino, guanidino,or a group represented by the following formula:—(C(R^(6e))(R^(6f)))_(f)—OR^(6g),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))(R^(6h)),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—C(═O)—R^(6h),—(C(R^(6e))(R^(6f)))_(f)—C(═O)—N(R^(6g))(R^(6h)),—(C(R^(6e))(R^(6f)))_(f)—O—C(═O)—N(R^(6g))(R^(6h)),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—C(═O)—N(R^(6h))(R^(6k)),—(C(R^(6e))(R^(6f)))_(f)—C(═O)—R^(6g),—(C(R^(6e))(R^(6f)))_(f)—C(═O)-G-(R^(6m))_(k),—(C(R^(6e))(R^(6f)))_(f)—CN, —(C(R^(6e))(R^(6f)))_(f)-G-(R^(6m))_(k),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—SO₂N(R^(6h))(R^(6k)),—(C(R^(6e))(R^(6f)))_(f)—SO₂R^(6g),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—SO₂R^(6h),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—C(═O)—OR^(6h),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—C(═O)-G-(R^(6m))_(k),—(C(R^(6e))(R^(6f)))_(f)—C(═O)—OR^(6g),—(C(R^(6e))(R^(6f)))_(f)—C(═O)—N(R^(6g))—(CH₂)_(f)—OR^(6h),—(C(R^(6e))(R^(6f)))_(f)—C(═O)—N(R^(6g))—(CH₂)_(f)—N(R^(6h))(R^(6k)),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—C(═O)—(CH₂)—OR^(6h),—(C(R^(6e))(R^(6f)))_(g)—N(R^(6g))—C(═O)—(CH₂)—O—C(═O)—N((R^(6h))(R^(6k)),or —(C(R^(6e))(R^(6f)))_(f)—O—(CH₂)₂—OR^(6g) wherein R^(6e) is eachindependently a hydrogen atom, halogen, alkyl or haloalkyl, R^(6f) iseach independently a hydrogen atom, halogen, alkyl or haloalkyl, or twoof R^(6e) which are attached to the adjacent carbons atom and/or two ofR^(6f) which are attached to the adjacent carbon atoms may be takentogether to form a bond; R^(6g) is a hydrogen atom, alkyl or haloalkyl;R^(6h) is a hydrogen atom, alkyl or haloalkyl; R^(6k) is a hydrogenatom, alkyl or haloalkyl; R^(6m) is each independently halogen, alkyl,haloalkyl, or a group represented by the following formula: —OR^(6n),—C(═O)—OR^(6n), —SO₂R^(6n), or —N(R^(6n))(R^(6p)), or two of R^(6m)which are attached to the same carbon atom may be taken together to formoxo, wherein R^(6n) is a hydrogen atom, alkyl or haloalkyl; R^(6p) is ahydrogen atom, alkyl or haloalkyl; f and k are each independently 0, 1,2 or 3; g is 1 or 2; provided that compounds wherein —X— is —S—, ═Y— is═CH— and —Z— is —S— are excluded; and provided that the followingcompounds are excluded:

or a pharmaceutically acceptable salt thereof.
 8. The compound accordingto claim 7, wherein —X— is —N(R³)— or —S—, ═Y— is ═CH—, and —Z— is —S—,provided that compounds wherein —X— is —S—, ═Y— is ═CH— and —Z— is —S—are excluded, or a pharmaceutically acceptable salt thereof.
 9. Thecompound according to claim 7, wherein a is 0, 1 or 2, b is 0, 1, 2 or3, and R^(2d) is each independently a hydrogen atom, halogen, alkyl,haloalkyl, or a group represented by the following formula: —OR^(2g),—O—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d), —C(═O)—R^(2g),—C(═O)—OR^(2g), —C(═O)N(R^(2g))(R^(2h)),—C(═O)—N(R^(2g))—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d), —SO₂R^(2g),—SO₂-E-(R^(2k))_(d), —N(R^(2g))—(C(R^(2e))(R^(2f)))_(c)-E-(R^(2k))_(d),—N(R^(2g))—C(═O)—R^(2h), —N(R^(2g))—C(═O)-E-(R^(2k))_(d), or-E-(R^(2k))_(d), wherein c is 0, 1 or 2, or a pharmaceuticallyacceptable salt thereof.
 10. The compound according to claim 7, whereinR³ is a hydrogen atom or a group represented by the following formula:-E-(R^(3c))_(d), wherein E is a benzene ring, or a pharmaceuticallyacceptable salt thereof.
 11. The compound according to claim 7, whereinR⁵ is alkyl, or a group represented by the following formula:—(C(R^(5e))(R^(5f)))_(e)—OR^(5g),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—R^(5h),—(C(R^(5e))(R^(5f)))_(e)—O—C(═O)—N(R^(5g))(R^(5h)),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—N(R^(5h))(R^(5k)),—(C(R^(5e))(R^(5f)))_(e)—CN, —(C(R^(5e))(R^(5f)))_(e)-G-(R^(5m))_(h),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—OR^(5h),—(C(R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)-G-(R^(5m))_(h), or—(C((R^(5e))(R^(5f)))_(e)—N(R^(5g))—C(═O)—(CH₂)—OR^(5h) wherein G is anon-aromatic heterocycle; and e is 1, 2 or 3, or a pharmaceuticallyacceptable salt thereof.
 12. The compound according to claim 7, whereinR⁶ is alkyl, or a group represented by the following formula:—(C(R^(6e))(R^(6f)))_(f)—OR^(6g),—(C((R^(6e))(R^(6f)))_(g)—N(R^(6g))(R^(6h)), or —C(R^(6e))(R^(6f))—CN,and f is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.
 13. Apharmaceutical composition comprising the compound according to claim 1,or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 14. A method of inhibiting a TRPV4 receptor in asubject, comprising administering an effective amount of thepharmaceutical composition according to claim 13 to the subject.
 15. Amethod for treating pain in a subject, which comprises administering aneffective amount of the compound according to claim 1, or apharmaceutically acceptable salt thereof, to the subject. 16-17.(canceled)